WO2011066389A1 - Targeted binding agents against b7-h1 - Google Patents

Targeted binding agents against b7-h1 Download PDF

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Publication number
WO2011066389A1
WO2011066389A1 PCT/US2010/058007 US2010058007W WO2011066389A1 WO 2011066389 A1 WO2011066389 A1 WO 2011066389A1 US 2010058007 W US2010058007 W US 2010058007W WO 2011066389 A1 WO2011066389 A1 WO 2011066389A1
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WIPO (PCT)
Prior art keywords
antibody
amino acid
seq
human
acid sequence
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PCT/US2010/058007
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French (fr)
Inventor
Christophe Queva
Michelle Morrow
Scott Hammond
Marat Alimzhanov
John Babcock
Ian Foltz
Jaspal Singh Kang
Laura Sekirov
Melanie Boyle
Matthieu Chodorge
Original Assignee
Medimmmune, Limited
Astrazeneca Ab
Amgen British Columbia
Medimmune, Llc
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Priority to MX2012005809A priority Critical patent/MX2012005809A/en
Priority to KR1020157031862A priority patent/KR101740171B1/en
Priority to EP17179204.7A priority patent/EP3279215B1/en
Application filed by Medimmmune, Limited, Astrazeneca Ab, Amgen British Columbia, Medimmune, Llc filed Critical Medimmmune, Limited
Priority to CN201080053042.1A priority patent/CN102918058B/en
Priority to LTEP10833923.5T priority patent/LT2504364T/en
Priority to AU2010324757A priority patent/AU2010324757C1/en
Priority to NZ599405A priority patent/NZ599405A/en
Priority to ES10833923.5T priority patent/ES2646863T3/en
Priority to MX2015000738A priority patent/MX343747B/en
Priority to MX2016015254A priority patent/MX359551B/en
Priority to PL10833923T priority patent/PL2504364T3/en
Priority to PL17179204T priority patent/PL3279215T3/en
Priority to JP2012540171A priority patent/JP5837504B2/en
Priority to US13/511,538 priority patent/US8779108B2/en
Priority to RU2012126138A priority patent/RU2571204C3/en
Priority to BR122021025338-2A priority patent/BR122021025338B1/en
Priority to RS20171053A priority patent/RS56469B1/en
Priority to BR112012012465-0A priority patent/BR112012012465B1/en
Priority to KR1020177030381A priority patent/KR101934071B1/en
Priority to KR1020177011850A priority patent/KR101790767B1/en
Priority to CA2778714A priority patent/CA2778714C/en
Priority to NO10833923A priority patent/NO2504364T3/no
Priority to SI201031562T priority patent/SI2504364T1/en
Priority to DK10833923.5T priority patent/DK2504364T3/en
Priority to EP10833923.5A priority patent/EP2504364B1/en
Publication of WO2011066389A1 publication Critical patent/WO2011066389A1/en
Priority to IL219876A priority patent/IL219876A/en
Priority to US14/271,108 priority patent/US9493565B2/en
Priority to IL243813A priority patent/IL243813A/en
Priority to AU2016203758A priority patent/AU2016203758C1/en
Priority to US15/333,683 priority patent/US10400039B2/en
Priority to HRP20171653TT priority patent/HRP20171653T1/en
Priority to CY20171101127T priority patent/CY1119743T1/en
Priority to FR19C1001C priority patent/FR19C1001I2/en
Priority to LTPA2019002C priority patent/LTC2504364I2/en
Priority to NL300964C priority patent/NL300964I2/en
Priority to HUS1900002C priority patent/HUS1900002I1/en
Priority to NO2019002C priority patent/NO2019002I1/no
Priority to CY2019003C priority patent/CY2019003I2/en
Priority to LU00097C priority patent/LUC00097I2/en
Priority to US16/519,614 priority patent/US11518809B2/en
Priority to CY20201100370T priority patent/CY1122816T1/en
Priority to US18/051,773 priority patent/US20230235062A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [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
    • C07K16/2827Immunoglobulins [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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567Framework region [FR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the invention relates to targeted binding agents against the B7-H1 protein and uses of such agents.
  • the invention relates to fully human monoclonal antibodies directed to B7-H1 and uses of these antibodies.
  • aspects of the invention also relate to cell lines expressing such targeted binding agents or antibodies.
  • the described targeted binding agents are useful as diagnostics and for the treatment of diseases associated with the activity and/or expression of B7-H1.
  • T cells and B cells Two major classes of lymphocytes termed T cells and B cells. After encountering an antigen, T cells proliferate and differentiate into antigen-specific effector cells, while B cells proliferate and differentiate into antibody-secreting cells.
  • T cell activation is a multi-step process requiring several signaling events between the T cell and an antigen-presenting cell (APC).
  • APC antigen-presenting cell
  • T cell activation to occur two types of signals must be delivered to a resting T cell. The first type is mediated by the antigen-specific T cell receptor (TcR), and confers specificity to the immune response. The second, costimulatory, type regulates the magnitude of the response and is delivered through accessory receptors on the T cell.
  • TcR antigen-specific T cell receptor
  • a primary costimulatory signal is delivered through the activating CD28 receptor upon engagement of its ligands B7-1 or B7-2.
  • engagement of the inhibitory CTLA-4 receptor by the same B7-1 or B7-2 ligands results in attenuation of a T cell response.
  • CTLA-4 signals antagonize costimulation mediated by CD28.
  • CD28 costimulation overrides the CTLA-4 inhibitory effect.
  • Temporal regulation of the CD28 and CTLA-4 expression maintains a balance between activating and inhibitory signals and ensures the development of an effective immune response, while safeguarding against the development of autoimmunity.
  • B7-H1 also known as PD-L1
  • B7-H1 is a type I transmembrane protein of approximately 53kDa in size.
  • B7-H1 is expressed on a number of immune cell types including activated and anergic/exhausted T cells, on na ' ive and activated B cells, as well as on myeloid dendritic cells (DC), monocytes and mast cells.
  • DC myeloid dendritic cells
  • non-immune cells including islets of the pancreas, Kupffer cells of the liver, vascular endothelium and selected epithelia, for example airway epithelia and renal tubule epithelia, where its expression is enhanced during inflammatory episodes.
  • B7-H1 expression is also found at increased levels on a number of tumours including, but not limited to breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), and pancreatic cancer, as well as melanoma.
  • NSCLC non-small cell lung cancer
  • HCC hepatocellular cancer
  • B7-H1 is a member of the B7 family of proteins, which contain two extracellular Ig domains, one N-terminal V-type domain followed by a C-type domain.
  • the intracellular domain of 30 amino acids length contains no obvious signaling motifs, but does bear a potential site for protein kinase C phosphorylation.
  • the murine form of B7-H1 bears 69% amino acid identity with the human form of B7-H1, and also shares a conserved structure.
  • B7-H1 is known to bind two alternative ligands, the first of these, PD-1, is a 50-55 kDa type I transmembrane receptor that was originally identified in a T cell line undergoing activation-induced apoptosis. PD-1 is expressed on activated T cells, B cells, and monocytes, as well as other cells of the immune system and binds both B7-H1 (PD-L1) and the related B7-DC (PD-L2). The second is the B7 family member B7-1, which is expressed on activated T cells, B cells, monocytes and antigen presenting cells.
  • PD-1 is a member of the immunoglobulin (Ig) superfamily that contains a single Ig V-like domain in its extracellular region.
  • the PD-1 cytoplasmic domain contains two tyrosines, with the most membrane-proximal tyrosine (VAYEEL in mouse PD-1) located within an ITIM (immuno- receptor tyrosine-based inhibitory motif).
  • ITIM immunoglobulin-based inhibitory motif
  • the ITIM in the cytoplasmic region and the ITIM-like motif surrounding the carboxy-terminal tyrosine (TEYATI in human and mouse) are also conserved between human and murine orthologues.
  • Signalling via the PD-1/B7-H1 axis is believed to serve critical, non-redundant functions within the immune system, by negatively regulating T cell responses. This regulation is involved in T cell development in the thymus, in regulation of chronic inflammatory responses and in maintenance of both peripheral tolerance and immune privilege.
  • the critical nature of these functions is exemplified in PD-1 -deficient mice, which exhibit an autoimmune phenotype. PD-1 deficiency in the C57BL/6 mice results in chronic progressive lupus-like glomerulonephritis and arthritis.
  • PD-1 deficiency leads to severe cardiomyopathy due to the presence of heart-tissue-specific self-reacting antibodies.
  • the function of signaling via B7-H1/B7-1 is less clear, but is thought to also be involved in delivering negative regulatory signals to both T cells and antigen presenting cells.
  • B7-H1 expression on tumour cells is believed to aid tumours in evading detection and elimination by the immune system.
  • B7-H1 functions in this respect via several alternative mechanisms including driving exhaustion and anergy of tumour infiltrating T lymphocytes, stimulating secretion of immune repressive cytokines into the tumour micro-environment, stimulating repressive regulatory T cell function and protecting B7-H1 expressing tumour cells from lysis by tumour cell specific cytotoxic T cells.
  • the present invention relates to targeted binding agents that specifically bind to B7-H1 and inhibit the biological activity of B7-H1.
  • the invention relates to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 activity.
  • the invention relates to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding of B7-H1 to PD-1.
  • the invention relates to targeted binding agents that block B7-H1 induced T-cell suppression and thereby enhance anti-tumor immunity.
  • the invention further relates to targeted binding agents that can further stimulate one or more of the following activities including T cell proliferation, IFN- ⁇ and/or IL-2 secretion in mixed lymphocyte reactions.
  • Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit the biological activity of B7- Hl .
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the biological activity than would occur in the absence of the targeted binding agent.
  • Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 activity.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 activity than would occur in the absence of the targeted binding agent.
  • Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding to PD-1.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1/PD-1 receptor ligand binding compared to what would occur in the absence of the targeted binding agent.
  • the targeted binding agents of the invention can inhibit binding of PD-l/Fc to human B7-H1 expressed on ES-2 cells.
  • the targeted binding agent inhibits binding with an IC50 of less than 1 nM, 0.5 nM, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07 or 0.06 nM.
  • the antibodies of the invention have an IC50 of about 1 nM down to about 0.06 nM; or of about 0.5 nM down to about 0.06 nM; or of about 0.1 nM down to about 0.06 nM; or of about 1 nM down to about 0.1 nM; or of about 1 nM down to about 0.5 nM.
  • Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding to its ligand B7-1.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 95%, 96%, 97%, 98% 99% or 100% of B7-H1/B7-1 receptor ligand binding compared to what would occur in the absence of the targeted binding agent.
  • Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit B7-H1 induced tumor proliferation.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 induced tumor proliferation than would occur in the absence of the targeted binding agent.
  • the targeted binding agent inhibits at least 5%, at least 10%>, at least 15%, at least 20%>, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 induced tumor cell survival than would occur in the absence of the targeted binding agent.
  • Targets of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit tumour growth of A375 or HPAC cancer cell lines.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%), or at least 95% of growth of cancer cells at day 30 compared to an isotype control.
  • Targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 mediated suppression of tumour reactive T-cells, thereby enhancing anti-tumour cytolytic T-cell activity.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 mediated suppression of tumour reactive T-cell activity than would occur in the absence of the targeted binding agent.
  • the targeted binding agent enhances at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of antitumor immunity than would occur in the absence of the targeted binding agent.
  • the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of cell proliferation than would occur in the absence of the targeted binding agent.
  • the antibodies of the invention relate to targeted binding agents that specifically bind to B7-H1 and increase specific cytolytic (CTL) activity against B7-H1 expressing tumor cells.
  • the antibodies of the invention have an EC50 of less than or equal to 100 nM, 50 nM or 1 nM. Further, in another embodiment, the antibodies of the invention have an EC50 of about 100 nM down to about 1 nM; or of about 50 nM down to about 1 nM; or of about 20 nM down to about 1 nM; or of about 100 nM down to about 50 nM; or of about 100 nM down to about 70 nM.
  • Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit B7-H1 mediated suppression of T-cell proliferation at an EC50 less than or equal to 100 nM.
  • the antibodies of the invention have an EC50 of less than or equal to 100 nM, e.g., 90, 80, 70, 60, 50, 40, 30, 20 or 10 nM.
  • the antibodies of the invention have an EC50 of about 100 nM down to about 10 nM; or of about 50 nM down to about 10 nM; or of about 20 nM down to about 10 nM; or of about 100 nM down to about 50 nM; or of about 100 nM down to about 70 nM; or of about 100 nM down to about 80 nM.
  • the targeted binding agents also inhibit tumour cell adhesion, motility, invasion and cellular metastasis and in addition, the targeted binding agents are useful for reducing tumour growth. Mechanisms by which this can be achieved can include, and are not limited to, inhibiting B7-H1 activity.
  • the targeted binding agent is an antibody. In one embodiment of the invention, the targeted binding agent is a monoclonal antibody. In one embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody or a fragment thereof. Such monoclonal antibodies may be referred to herein as anti-B7-Hl antibodies or antibodies of the invention.
  • Antibodies, monoclonal antibodies and human monoclonal antibodies include the antibodies of the IgGl, IgG2, IgG3 and IgG4 isotypes, for example IgG2.
  • the targeted binding agent is a fully human monoclonal antibody of the IgG2 isotype. This isotype has reduced potential to elicit effector function in comparison with other isotypes, which may lead to reduced toxicity.
  • the targeted binding agent is a fully human monoclonal antibody of the IgGl isotype.
  • the IgGl isotype has increased potential to elicit Antibody Directed Cell-mediated Cytotoxicity (ADCC) in comparison with other isotypes, which may lead to improved efficacy.
  • ADCC Antibody Directed Cell-mediated Cytotoxicity
  • the IgGl isotype has improved stability in comparison with other isotypes, e.g. IgG4, which may lead to improved bioavailability/ease of manufacture/longer half-life.
  • the fully human monoclonal antibody of the IgGl isotype is of the z, za or f allotype.
  • the targeted binding agent has desirable therapeutic properties, selected from one or more of the following: high binding affinity for B7-H1, the ability to inhibit B7-H1 activity in vitro and in vivo, the ability to inhibit B7-H1 -mediated tumour cell survival, and the ability to inhibit B7-H1 mediated suppression of tumour reactive T-cells, which may in turn reduce tumour cell proliferation, motility, invasion, metastasis, and tumour growth.
  • the invention includes antibodies that specifically bind to B7-H1 with very high affinities (Kd).
  • the targeted binding agent binds B7-H1 with a binding affinity (Kd) of less than 5 nanomolar (nM). In other embodiments, the targeted binding agent binds with a Kd of less than 4 nM, 3 nM, 2.5nM, 2 nM or 1 nM.
  • antibodies of the invention binds B7-H1 with a Kd of about 5 nM to about 1 nM; or about 5 nM to about 2 nM; or about 5 nM to about 3 nM; or about 5 nM to about 4 nM; or about 3 nM to about 1 nM; or about 2 nM to about 1 nM.
  • the targeted binding agent binds B7-H1 with a Kd of less than 950 picomolar (pM).
  • the targeted binding agent binds B7-H1 with a Kd of less than 900 pM.
  • the targeted binding agent binds B7-H1 with a Kd of less than 800 pM, 700 pM or 600 pM. In some embodiments of the invention, the targeted binding agent binds B7-H1 with a Kd of less than 500 pM. In other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 400 pM. In still other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 300 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 200 pM.
  • the targeted binding agent binds B7-H1 with a Kd of less than 100 pM.
  • antibodies of the invention binds B7-H1 with a Kd of about 900 pM to about 100 pM; or about 900 pM to about 200 pM; or about 900 pM to about 300 pM; or about 900 pM to about 400 pM; or about 900 pM to about 500 pM; or about 900 pM to about 600 pM; or about 900 pM to about 700 pM; or about 200 pM to about 100 pM; or about 300 pM to about 200 pM; or about 400 pM to about 300 pM.
  • the targeted binding agent binds B7-H1 with a Kd of less than 90 pM, 80 pM, 70 pM, 60 pM, 55pM or 50pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 60 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 55 pM.
  • antibodies of the invention binds B7-H1 with a Kd of about 100 pM to about 50 pM; or about 100 pM to about 70 pM; or about 100 pM to about 80 pM; or about 100 pM to about 90 pM; or about 70 pM to about 50 pM; or about 60 pM to about 50 pM; or about 55 pM to about 50 pM.
  • the Kd may be assessed using a method described herein or known to one of skill in the art (e.g., a BIAcore assay, ELISA) (Biacore International AB, Uppsala, Sweden).
  • Targeted binding agents of the invention have considerably improved binding affinities for B7-H1 in comparison with the antibodies reported in the prior art.
  • binding properties of the targeted binding agent or antibody of the invention may also be measured by reference to the dissociation or association rates (k 0ff and k on respectively).
  • a targeted binding agent or an antibody of the invention may have a k on rate (antibody (Ab) + antigen (Ag) kon — Ab- Ag) of at least 10 4 M ' V 1 , at least 5 X 10 4 M ' V 1 , at least 10 5 M ' V 1 , at least 2 X 10 5 M ' V 1 , at least 5 X 10 5 M ' V 1 , at least 10 6 M ' V 1 , at least 5 X 10 6 M ' V 1 , at least 10 7 M ' V 1 , at least 5 X 10 7 M ' V 1 , or at least 10 8 M ' V 1 as measured by a BIAcore assay.
  • antibodies of the invention have a k on rate of about 5 X 10 4 M ' V 1 to about 5 X 10 8 M ' V 1 ; or of about 5 X 10 5 M " V 1 to about 5 X 10 8 M ' V 1 ; or of about 5 X 10 6 M ' V 1 to about 5 X 10 8 M ' V 1 ; or of about 5 X 10 7 M ' V 1 to about 5 X 10 8 M ' V 1 , as measured by a BIAcore assay.
  • targeted binding agent or an antibody may have a k 0 ff rate ( (Ab-Ag) ko ⁇ antibody (Ab) + antigen (Ag)) of less than 5x10 "1 s "1 , less than 10 "1 s "1 ,
  • antibodies of the invention have a k 0 ff rate of about 1 X 10 "4 s “1 to about 1 X 10 "5 s “1 ; or of about 1 X 10 "4 s “1 to about 5 X 10 "4 s “1 ,as measured by a BIAcore assay.
  • the targeted binding agent of the invention specifically binds human B7-H1.
  • the targeted binding agent of the invention does not bind other immune co-modulatory proteins, e.g., human PD-L2, human B7-H2, human B7-H3, human CD28, human CTLA-4 and human PD1.
  • the targeted binding agent of the invention is cross-reactive with other B7-H1 proteins from other species.
  • the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1.
  • the targeted binding agent of the invention is cross-reactive with mouse B7-H1, e.g., 2.7A4.
  • the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1 and with mouse B7-H1, e.g., 2.7A4.
  • the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1 but not with mouse B7- Hl, e.g., 2.9D10 and 2.14H9.
  • the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences (VH) shown in Table 8. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT.
  • a targeted binding agent or antibody comprising a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT, or another antibody as disclosed herein, may further comprise any one of the light chain sequences (VL) shown in Table 9 or of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT or 2.14H90PT, or other antibody as disclosed herein.
  • VL light chain sequences
  • the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT and further comprising the corresponding light chain sequence of antibody 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT.
  • the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody comprises a sequence comprising any one of the light chain sequences shown in Table 9. In another embodiment, the targeted binding agent or antibody comprises a sequence comprising any one of the light chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.7A4 and further comprising the light chain sequence of antibody 2.7A4. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.14H9 and further comprising the light chain sequence of antibody 2.14H9. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.9D10 and further comprising the light chain sequence of antibody 2.9D10. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.7A.40PT and further comprising the light chain sequence of antibody 2.7A.40PT. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.14H90PT and further comprising the light chain sequence of antibody 2.14H90PT.
  • the targeting binding agent is any one of the monoclonal antibodies as shown in Table 1.
  • the targeting binding agent is a monoclonal antibody selected from the group consisting of: 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT.
  • the targeted binding agent comprises one or more of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT.
  • the targeting binding agent is monoclonal antibody 2.7A4.
  • the targeting binding agent is monoclonal antibody 2.14H9.
  • the targeting binding agent is monoclonal antibody 2.9D10.
  • the targeting binding agent is monoclonal antibody 2.7A40PT. In certain other embodiments, the targeting binding agent is monoclonal antibody 2.14H90PT. In additional embodiments, the targeted binding agent is derivable from any of the foregoing monoclonal antibodies.
  • the targeted binding agent may comprise a sequence comprising any one of the CDR1, CDR2 or CDR3 of the heavy chain variable sequences encoded by a polynucleotide in a plasmid designated 2.7A4 G, 2.14H9 G, and 2.9D10 NG which were deposited at NCIMB under number 41598 on November 19, 2008, under number 41597 on November 19, 2008, and under number 41599 on November 19, 2008, respectively.
  • the targeted binding agent may comprise a sequence comprising any one of the CDR1, CDR2 or CDR3 of the light chain variable domain sequences encoded by a polynucleotide in a plasmid designated 2.7A4 G, 2.14H9 G and 2.9D10 NG which were deposited under number 41598 on November 19, 2008, under number 41597 on November 19, 2008, or under number 41599 on November 19, 2008, respectively.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008 and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008, and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19,
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19,
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under number 41598 on November 19, 2008 and a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under number 41598 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008 and a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
  • a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
  • a targeted binding agent or an antibody may comprise a sequence comprising a heavy chain CDR1 (HCDRl), heavy chain CDR2 (HCDR2) and heavy chain CDR3 (HCDR3) selected from any one of the sequences shown in Table 8.
  • a targeted binding agent or an antibody may comprise a sequence comprising a light chain CDR1 (LCDRl), light chain CDR2 (LCDR2) and light chain CDR3 (LCDR3) selected from any one of the sequences shown in Table 9.
  • a targeted binding agent or an antibody may comprise a sequence comprising a HCDRl, HCDR2 and HCDR3 selected from any one of the CDRs of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, or 3.18G1.
  • a targeted binding agent or an antibody may comprise a sequence comprising a LCDRl, LCDR2 and LCDR3 selected from any one of the CDRs of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, or 3.18Gl .
  • a further embodiment is a targeted binding agent or an antibody that specifically binds to B7-H1 and comprises a sequence comprising one of the CDR2 and one of the CDR3 sequences shown in Table 9.
  • the targeted binding agent or antibody further comprises a sequence comprising: a CDR3 sequence as shown in Table 8.
  • the targeted binding agent or antibody further comprises a sequence comprising: a CDR2 and a CDR3 sequence as shown in Table 8 and/or Table 9.
  • the targeted binding agent or antibody further comprises a sequence comprising: a CDRl, a CDR2 and a CDR3 sequence as shown in Table 8 and/or Table 9.
  • the targeted binding agent or antibody may comprise a sequence comprising any one of a CDRl, a CDR2 or a CDR3 of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, as shown in Table 8.
  • the targeted binding agent or antibody may comprise a sequence comprising any one of a CDRl, a CDR2 or a CDR3 of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, as shown in Table 9.
  • the targeted binding agent or antibody may comprise a sequence comprising a CDRl, a CDR2 and a CDR3 of any one of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT, as shown in Table 8.
  • the targeted binding agent or antibody may comprise a sequence comprising a CDRl, a CDR2 and a CDR3 of any one of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT, as shown in Table 9.
  • the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.7A4 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.7A4 as shown in Table 9.
  • the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.14H9 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.14H9 as shown in Table 9.
  • the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.9D10 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.9D10 as shown in Table 9.
  • the antibody is a fully human monoclonal antibody.
  • a further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT, or as shown in Table 8 or Table 9.
  • a further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 and Table 9.
  • the targeted binding agent or antibody comprises a sequence comprising the contiguous sequences spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences of monoclonal antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 or Table 9.
  • a further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences of monoclonal antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 and Table 9.
  • the antibody is a fully human monoclonal antibody.
  • a targeted binding agent or antibody of the invention comprises a CDR3 sequence as shown in Table 8 or 9; or any one of a CDRl, a CDR2 or a CDR3 sequence as shown in Table 8 or 9; or a CDRl, a CDR2 and a CDR3 sequence of a light chain variable domain sequence as shown in Table 8; or a CDRl, a CDR2 and a CDR3 sequence of a heavy chain variable domain sequence sequence as shown as shown in Table 9.
  • One embodiment provides a targeted binding agent or antibody, or antigen-binding portion thereof, wherein the agent or antibody, or antigen-binding portion thereof, comprises a sequence comprising SEQ ID NO.:2, SEQ ID NO.:7, SEQ ID NO.: 12, SEQ ID NO.: 17, SEQ ID NO.:22, SEQ ID NO.:27, SEQ ID NO.:32, SEQ ID NO.:37, SEQ ID NO.:42, SEQ ID NO.:47, SEQ ID NO.:52, SEQ ID NO.:57, SEQ ID NO.:62, SEQ ID NO.:67, SEQ ID NO.:72, or SEQ ID NO.:77.
  • One embodiment provides a targeted binding agent or antibody, or antigen-binding portion thereof, wherein the agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:2.
  • the targeted binding agent or antibody, or antigen-binding portion thereof further comprises a light chain sequence comprising the sequence of SEQ ID NO.:7.
  • the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:2 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:7.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.: 12. In one embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.: 17. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 12 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 17.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:22. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:27. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:22 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:27.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:32.
  • the targeted binding agent or antibody, or antigen-binding portion thereof further comprises a light chain sequence comprising the sequence of SEQ ID NO.:37.
  • the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:32 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:37.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:42. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:47. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:42 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:47.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:52. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:57. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:52 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:57.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:62. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:67. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 62 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 67.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.: 72. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:77. In some embodiments, the antibody is a fully human monoclonal antibody.
  • the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 72 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 77.
  • the targeted binding agent or antibody comprises variants or derivatives of the CDRs disclosed herein, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3), the light or heavy chain sequences disclosed herein, or the antibodies disclosed herein.
  • Variants include targeted binding agents or antibodies comprising sequences which have as many as twenty, sixteen, ten, nine or fewer, e.g.
  • Variants include targeted binding agents or antibodies comprising sequences which have one, two or three, amino acid additions, substitutions, deletions, and/or insertions in any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein.
  • Variants include targeted binding agents or antibodies comprising sequences which have at least about 60, 70, 80, 85, 90, 95, 98 or about 99% amino acid sequence identity with any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FR1 through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein.
  • the percent identity of two amino acid sequences can be determined by any method known to one skilled in the art, including, but not limited to, pairwise protein alignment.
  • variants comprise changes in the CDR sequences or light or heavy chain sequences disclosed herein that are naturally occurring or are introduced by in vitro engineering of native sequences using recombinant DNA techniques or mutagenesis techniques.
  • Naturally occurring variants include those which are generated in vivo in the corresponding germline nucleotide sequences during the generation of an antibody to a foreign antigen.
  • variants include targeted binding agents or antibodies comprising sequences which have (a) a VH CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 3;
  • VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 4;
  • VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 5;
  • VL CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to VL CDRl of SEQ ID NO: 8;
  • VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 9;
  • VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 10.
  • variants include targeted binding agents or antibodies comprising sequences which have (a) a VH CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 23;
  • VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 24
  • VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 25;
  • VL CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to VL CDR1 of SEQ ID NO: 28;
  • VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 29;
  • VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 30.
  • the derivative may be a heteroantibody, that is an antibody in which two or more antibodies are linked together.
  • Derivatives include antibodies which have been chemically modified. Examples include covalent attachment of one or more polymers, such as water-soluble polymers, N-linked, or O-linked carbohydrates, sugars, phosphates, and/or other such molecules. The derivatives are modified in a manner that is different from naturally occurring or starting antibody, either in the type or location of the molecules attached. Derivatives further include deletion of one or more chemical groups which are naturally present on the antibody.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one, any two, any three, any four or all five of the germline residues as indicated in Table 10.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 10.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7, wherein SEQ ID NO.: 7 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11 and any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7, wherein SEQ ID NO.: 7 comprises any one, any two, any three, any four, any five, for all five of the germline residues as indicated in Table 11.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12, wherein SEQ ID NO.: 12 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 12. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12, wherein SEQ ID NO.: 12 comprises any one, any two or all two of the germline residues as indicated in Table 12.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17, wherein SEQ ID NO.: 17 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 13. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17, wherein SEQ ID NO.: 17 comprises any one, any two, any three, any four or all four of the germline residues as indicated in Table 13.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27, wherein SEQ ID NO.: 27 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 14. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27, wherein SEQ ID NO.: 27 comprises any one, any two, any three or all three of the germline residues as indicated in Table 14.
  • a further embodiment of the invention is a targeted binding agent or antibody which competes for binding to B7-H1 with the targeted binding agent or antibodies of the invention.
  • the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
  • “Competes” indicates that the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT, i.e. competition is unidirectional.
  • Embodiments of the invention include a targeted binding agent or antibody which cross competes with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT for binding to B7-H1.
  • Cross competes indicates that the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT, and vice versa, i.e. competition is bidirectional.
  • a further embodiment of the invention is a targeted binding agent or antibody that binds to the same epitope or epitopes on the extracellular domain of human B7-H1 as the targeted binding agent or antibodies of the invention.
  • Embodiments of the invention also include a targeted binding agent or antibody that binds to the same epitope or epitopes on the extracellular domain of human B7-H1 as any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
  • the targeted binding agent or antibody binds an epitope on human
  • B7-H1 including at least one or more of the following amino acids selected from the group consisting of Asp at position 122 and Arg at position 125.
  • an antibody of the invention binds an epitope on human B7-H1 comprising at least two of the following three amino acid residues of Asp at position 122, Arg at position 125 and Arg at position 113.
  • the antibody binds an epitope on human B7-H1, wherein the antibody exhibits no binding to He at position 54, Ser at position 117 and Ala at position 121 on human B7-H1.
  • an antibody of the invention loses its ability to bind to human B7-H1 if the Arg at position 113 is mutated to an Ala, or to a Tyr, or to a Leu as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Arg at position 125 is mutated to an Ala, or to a Gin, or to a Ser as determined by a competition assay as compared to binding to wild-type B7-H1.
  • an antibody of the invention retains its ability to bind to human B7-H1 if the Arg at position 123 is mutated to an Ala, or to a Phe, or to a Thr as determined by a competition assay as compared to binding to wild-type B7-H1.
  • the antibody is 2.14H9.
  • the antibody is 2.14H90PT.
  • the targeted binding agent or antibody binds an epitope on the extracellular domain of human B7-H1 comprising at least one or more of the following amino acids Asp at position 122 and Thr at position 20.
  • the antibody binds at least two of the following three amino acid residues of Phe at position 19, Thr at position 20 and Asp at position 122 on human B7-H1.
  • an antibody of the invention loses its ability to bind to human B7-H1 if the Phe at position 19 is mutated to an Ala, or to a Gly, or to a Ser as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Thr at position 20 is mutated to an Ala, or to a Val, or to a Asp as
  • an antibody of the invention loses its ability to bind to human B7-H1 if the Asp at position 122 is mutated to an Asn, or to a Glu as determined by a competition assay as compared to binding to wild-type B7-H1.
  • an antibody of the invention retains its ability to bind to human B7-H1 if the Arg at position 123 is mutated to an Ala, or to a Phe, or to a Thr as determined by a competition assay as compared to binding to wild-type B7-H1.
  • the antibody is 2.7A4. In another example, the antibody is 2.7A40PT.
  • the targeted binding agent is a bispecific antibody.
  • a bispecific antibody is an antibody that has binding specificity for at least two different epitopes on the same or on different proteins. Methods for making bispecific antibodies are known in the art. (See, for example, Millstein et al, Nature, 305:537-539 (1983); Traunecker et al., EMBO J, 10:3655- 3659 (1991); Suresh et al, Methods in Enzymology, 121 :210 (1986); Kostelny et al., J. Immunol, 148(5): 1547-1553 (1992); Hollinger et al, Proc. Natl Acad. Sci.
  • Embodiments of the invention described herein relate to monoclonal antibodies that specifically bind B7-H1 and affect B7-H1 function.
  • Other embodiments relate to fully human antibodies that specifically bind B7-H1 and preparations thereof with desirable properties from a therapeutic perspective, including high binding affinity for B7-H1, high selectivity for inhibition of B7-H1 signaling, low toxicity, the ability to block PD-1 receptor activity, the ability to inhibit B7-H1 -induced tumour cell survival through immune suppression, the ability to inhibit B7-H1 mediated repression of anti-tumour immunity, which may in turn inhibit proliferation or invasion -related diseases include neoplastic diseases, and/or the ability of tumour cells to grow in vitro and in vivo.
  • Still other embodiments relate to a method of repressing B7-H1 -mediated T cell inhibition in an animal by administering to an animal in need thereof an effective amount of a composition comprising the antibodies of the invention. Still other embodiments relate to fully human antibodies that specifically bind B7-H1 and preparations thereof that do not result in a significant Human Anti-Chimeric Antibody (HACA) response, thereby allowing for repeated administration.
  • HACA Human Anti-Chimeric Antibody
  • nucleic acid molecule encoding any of the targeted binding agents or antibodies of the invention.
  • nucleic acid molecule encoding the light chain or the heavy chain of an antibody of the invention.
  • nucleic acid molecule encodes the light chain or the heavy chain of a fully human monoclonal antibody of any of the antibodies described herein.
  • nucleic acid molecule encodes the light chain or the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • the nucleic acid molecule encodes the light chain and the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • the invention also encompasses polynucleotides that hybridize under stringent or lower stringency hybridization conditions, as defined herein, to polynucleotides that encode any of the targeted binding agents or antibodies described herein.
  • a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a targeted binding agent as described hereinabove.
  • a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a light chain and/or a heavy chain of an antibody as defined hereinabove.
  • the vector comprises a nucleic acid molecule encoding the light chain and/or the heavy chain of a fully human monoclonal antibody.
  • the vector comprises a nucleic acid molecule encoding the light chain or the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. In another embodiment, the vector comprises a nucleic acid molecule encoding the light chain and the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • a host cell transformed with any of the nucleic acid molecules as described hereinabove.
  • a host cell comprising the vector comprising the nucleic acid molecule as described hereinabove.
  • the host cell may comprise more than one vector.
  • antibodies can advantageously be, for example, polyclonal, oligoclonal, monoclonal, chimeric, humanised, and/or fully human antibodies.
  • the targeted binding agent is a binding fragment of a fully human monoclonal antibody.
  • the targeted binding agent can be a full-length antibody (e.g., having an intact human Fc region) or an antibody binding fragment (e.g., a Fab, Fab' or F(ab') 2 , Fv, dAb or other well known antibody fragment, as described in more detail below).
  • the antibodies can be single-domain antibodies such as camelid or human single VH or VL domains that bind to B7-H1, such as a dAb fragment.
  • Embodiments of the invention described herein also provide cells for producing these antibodies.
  • Examples of cells include hybridomas, or recombinantly created cells, such as Chinese hamster ovary (CHO) cells, variants of CHO cells (for example DG44) and NSO cells that produce antibodies against B7-H1. Additional information about variants of CHO cells can be found in Andersen and Reilly (2004) Current Opinion in Biotechnology 15, 456-462 which is incorporated herein in its entirety by reference.
  • the antibody can be manufactured from a hybridoma that secretes the antibody, or from a recombinantly engineered cell that has been transformed or transfected with a gene or genes encoding the antibody.
  • one embodiment of the invention is a method of producing a targeted binding agent or an antibody of the invention by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the targeted binding agent or antibody followed by recovery of the targeted binding agent or antibody.
  • a method of producing an antibody of the invention by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the antibody, followed by recovery of the antibody.
  • Still other embodiments include an antibody of the invention produced by the method of culturing a host cell which expresses an antibody encoded by a nucleic acid molecule encoding an antibody of the invention, and isolating said antibody from said culture.
  • embodiments of the invention also include any nucleic acid molecule which encodes an antibody or fragment of an antibody of the invention including nucleic acid sequences optimised for increasing yields of antibodies or fragments thereof when transfected into host cells for antibody production.
  • a further embodiment herein includes a method of producing antibodies that specifically bind to B7-H1 and inhibit the biological activity of B7-H1, by immunising a mammal with cells expressing B7-H1, isolated cell membranes containing B7-H1, purified B7-H1, or a fragment thereof, and/or one or more orthologous sequences or fragments thereof.
  • a further embodiment herein includes a method of producing high affinity antibodies that specifically bind to B7-H1 and inhibit the biological activity of B7-H1, by immunising a mammal with cells expressing B7-H1, isolated cell membranes containing B7-H1, purified B7- Hl, or a fragment thereof, and/or one or more orthologous sequences or fragments thereof.
  • Other embodiments are based upon the generation and identification of isolated antibodies that bind specifically to B7-H1 and inhibit the biological activity of B7-H1.
  • B7-H1 is expressed on a number of tumour types.
  • Antibodies that specifically bind to B7-H1 can prevent B7-H1 -mediated tumour cell survival and inhibit B7-H1 mediated repression of anti-tumour immune responses through immune suppression, this can in turn reduce tumour cell invasion, metastasis, tumour growth, and other properties.
  • the antibody can be manufactured from a hybridoma that secretes the antibody, or from a recombinantly engineered cell that has been transformed or transfected with a gene or genes encoding the antibody.
  • a hybridoma that produces the targeted binding agent or antibody of the invention there is a hybridoma that produces the light chain and/or the heavy chain of an antibody of the invention.
  • the hybridoma may produce a light chain and/or a heavy chain of a fully human monoclonal antibody.
  • the hybridoma produces the light chain and/or the heavy chain of the fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • the hybridoma may produce an antibody that binds to the same epitope or epitopes as fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • the hybridoma may produce an antibody that competes for binding to B7-H1 with fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • the hybridoma may produce an antibody that cross-competes for binding to B7-H1 with fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
  • compositions including a targeted binding agent or antibody of the invention or binding fragment thereof, and a pharmaceutically acceptable carrier.
  • Still further embodiments of the invention include methods of treating a proliferative or invasion-related disease in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for a proliferative or invasion-related disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the animal is human.
  • the targeted binding agent is a fully human monoclonal antibody.
  • the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
  • Still further embodiments of the invention include methods of inhibiting cell proliferation or invasion -related disease, with a B7-H1 mediated component, in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for proliferation or invasion -related disease, with a B7-H1 mediated component, and administering to said animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the animal is human.
  • the targeted binding agent is a fully human monoclonal antibody.
  • the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
  • Still further embodiments of the invention include methods of inhibiting tumour cell invasion, cellular metastasis or tumour growth in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for tumour cell, invasion, cellular metastasis or tumour growth, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the animal is human.
  • the targeted binding agent is a fully human monoclonal antibody.
  • the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
  • Still further embodiments of the invention include methods of treating an animal suffering from a neoplastic disease by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for a neoplastic disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • Still further embodiments of the invention include methods of treating an animal suffering from a non-neoplastic disease by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for a non-neoplastic disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • Still further embodiments of the invention include methods of treating an animal suffering from chronic viral infection by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for chronic viral infection, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • Still further embodiments of the invention include methods of treating an animal suffering from a malignant tumour by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for a malignant tumour, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • Still further embodiments of the invention include methods of treating an animal suffering from a disease or condition associated with B7-H1 expression by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • the method further comprises selecting an animal in need of treatment for a disease or condition associated with B7-H1 expression, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
  • a malignant tumour may be selected from the group consisting of: solid tumours such as melanoma, skin cancers, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, gallbladder cancer, thyroid tumour, bone cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, testicular cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, renal cell carcinoma, colon cancer, colorectal, pancreatic cancer, esophageal carcinoma, brain/CNS cancers, head and neck cancers, neuronal cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma, sarcomas, cancer of the pleural/peritoneal membranes and le
  • Treatable proliferative or invasion -related diseases include neoplastic diseases, such as, melanoma, skin cancer, small cell lung cancer, non-small cell lung cancer, salivary gland, glioma, hepatocellular (liver) carcinoma, gallbladder cancer, thyroid tumour, bone cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, testicular cancer, bladder cancer, lung cancer, glioblastoma, thyroid cancer, endometrial cancer, kidney cancer, colon cancer, colorectal cancer, pancreatic cancer, esophageal carcinoma, brain/CNS cancers, neuronal cancers, head and neck cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma, sarcomas, cancer of the pleural/
  • Treatable chronic viral infections include HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) in humans, simian immunodeficiency virus (SIV) in monkeys, and lymphocytic choriomeningitis virus (LCMV) in mice.
  • HIV hepatitis B virus
  • HCV hepatitis C virus
  • SIV simian immunodeficiency virus
  • LCMV lymphocytic choriomeningitis virus
  • Disease-related cell invasion and/or proliferation may be any abnormal, undesirable or pathological cell invasion and/or proliferation, for example tumour-related cell invasion and/or proliferation.
  • the neoplastic disease is a solid tumour selected from any one of the following carcinomas of the breast, colon, colorectal, prostate, stomach, gastric, ovary, esophagus, pancreas, gallbladder, non-small cell lung cancer, thyroid, endometrium, head and neck, renal, renal cell carcinoma, bladder and gliomas.
  • the present invention is suitable for use in inhibiting B7-H1, in patients with a tumour which is dependent alone, or in part, on B7-H1.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a proliferative or invasion-related disease.
  • the use further comprises selecting an animal in need of treatment for a proliferative or invasion-related disease.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of medicament for the treatment of proliferation or invasion -related disease, with a B7-H1 mediated component, in an animal.
  • the use further comprises selecting an animal in need of treatment for proliferation or invasion -related disease, with a B7-H1 mediated component.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of medicament for the treatment of tumour cell invasion, cellular metastasis or tumour growth in an animal.
  • the use further comprises selecting an animal in need of treatment for tumour cell invasion, cellular metastasis or tumour.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a neoplastic disease.
  • the use further comprises selecting an animal in need of treatment for a neoplastic disease.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a disease where the etiology is associated with an infectious agent, such as, for example, hepatocellular cancer, gastric cancer, or cervical cancer.
  • an infectious agent such as, for example, hepatocellular cancer, gastric cancer, or cervical cancer.
  • the use further comprises selecting an animal in need of treatment for a neoplastic disease.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a non-neoplastic disease.
  • the use further comprises selecting an animal in need of treatment for a non-neoplastic disease.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from chronic viral infection.
  • the use further comprises selecting an animal in need of treatment for a non-neoplastic disease.
  • the use further comprises ocular disease, inflammatory disease, cardiovascular disease and sepsis.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a malignant tumour.
  • the use further comprises selecting an animal in need of treatment for a malignant tumour.
  • Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a disease or condition associated with B7-H1 expression.
  • the use further comprises selecting an animal in need of treatment for a disease or condition associated with B7-H1 expression.
  • Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from a proliferative or invasion-related disease.
  • Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from tumour cell invasion, cellular metastasis or tumour growth in an animal.
  • Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from a disease or condition associated with B7-H1 expression.
  • treatment of a proliferative or invasion-related disease In one embodiment treatment of a proliferative or invasion-related disease
  • treatment of a neoplastic disease comprises inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, increased time to tumour recurrence, slowing of disease progression.
  • treatment of a disease or condition associated with B7-H1 expression comprises inhibiting the growth of cells that express B7-H1.
  • a clearing agent is administered, to remove excess circulating antibody from the blood.
  • the animal to be treated is a human.
  • the targeted binding agent is a fully human monoclonal antibody.
  • the targeted binding agent is selected from the group consisting of fully human monoclonal antibodies 2.7A4, 2.14H9 and 2.9D10.
  • Embodiments of the invention include a conjugate comprising the targeted binding agent as described herein, and a therapeutic agent.
  • the therapeutic agent is a toxin.
  • the therapeutic agent is a radioisotope.
  • the therapeutic agent is a pharmaceutical composition.
  • a method of selectively killing a cancerous cell in a patient comprises administering a fully human antibody conjugate to a patient.
  • the fully human antibody conjugate comprises an antibody that can bind to B7-H1 and an agent.
  • the agent is either a toxin, a radioisotope, or another substance that will kill a cancer cell.
  • the antibody conjugate thereby selectively kills the cancer cell.
  • a conjugated fully human antibody that specifically binds to B7-H1 is provided. Attached to the antibody is an agent, and the binding of the antibody to a cell results in the delivery of the agent to the cell.
  • the above conjugated fully human antibody binds to an extracellular domain of B7-H1.
  • the antibody and conjugated toxin are internalised by a cell that expresses B7-H1.
  • the agent is a cytotoxic agent.
  • the agent is, for example saporin, or auristatin, pseudomonas exotoxin, gelonin, ricin, calicheamicin or maytansine -based immunoconjugates, and the like.
  • the agent is a radioisotope.
  • the targeted binding agent or antibody of the invention can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drugs or radiation therapy or therapeutic vaccines.
  • a monoclonal, oligoclonal or polyclonal mixture of B7-H1 antibodies that block B7-H1 mediated repression of anti-tumour immunity can be administered in combination with a drug shown to inhibit tumour cell proliferation.
  • a pharmaceutical composition comprising a targeted binding agent of antibody of the invention and a pharmaceutically acceptable carrier.
  • Another embodiment of the invention includes a method of diagnosing diseases or conditions in which an antibody as disclosed herein is utilised to detect the presence and/or level of B7-H1 in a patient or patient sample.
  • the patient sample is blood or blood serum or urine.
  • methods for the identification of risk factors, diagnosis of disease, and staging of disease is presented which involves the identification of the expression and/or overexpression of B7-H1 using anti-B7-Hl antibodies.
  • the methods comprise administering to a patient a fully human antibody conjugate that selectively binds to B7-H1 on a cell.
  • the antibody conjugate comprises an antibody that specifically binds to B7-H1 and a label.
  • the methods further comprise observing the presence of the label in the patient. A relatively high amount of the label will indicate a relatively high risk of the disease and a relatively low amount of the label will indicate a relatively low risk of the disease.
  • the label is a green fluorescent protein.
  • the invention further provides methods for assaying for the presence and/or level of B7- HI in a patient sample, comprising contacting an antibody as disclosed herein with a biological sample from a patient, and detecting the level of binding between said antibody and B7-H1 in said sample.
  • the biological sample is blood, plasma or serum.
  • Another embodiment of the invention includes a method for diagnosing a condition associated with the expression of B7-H1 in a cell by contacting the serum or a cell with an antibody as disclosed herein, and thereafter detecting the presence of B7-H1.
  • the condition can be a proliferative or invasion -related disease including, but not limited to, a neoplastic disease.
  • the invention includes an assay kit for detecting B7-H1 in mammalian tissues, cells, or body fluids. Such a kit would be useful to screen for B7-H1 -related diseases.
  • the kit includes a targeted binding agent or antibody of the invention and a means for indicating the reaction of the targeted binding agent or antibody with B7-H1, if present.
  • the antibody is a monoclonal antibody.
  • the antibody that binds B7-H1 is labeled.
  • the antibody is an unlabeled primary antibody and the kit further includes a means for detecting the primary antibody.
  • the means for detecting includes a labeled second antibody that is an anti-immunoglobulin.
  • the antibody may be labeled with a marker selected from the group consisting of a fluorochrome, an enzyme, a radionuclide and a radiopaque material.
  • the targeted binding agents or antibodies as disclosed herein can be modified to enhance their capability of fixing complement and participating in complement- dependent cytotoxicity (CDC).
  • the targeted binding agents or antibodies can be modified to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC).
  • the targeted binding agents or antibodies can be modified both to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to enhance their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).
  • the targeted binding agents or antibodies as disclosed herein can be modified to reduce their capability of fixing complement and participating in complement- dependent cytotoxicity (CDC). In other embodiments, the targeted binding agents or antibodies can be modified to reduce their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC). In yet other embodiments, the targeted binding agents or antibodies as disclosed herein can be modified both to reduce their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to reduce their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cytotoxicity
  • the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 4 to 7 days.
  • the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 2 to 5 days, 3 to 6 days, 4 to 7 days, 5 to 8 days, 6 to 9 days, 7 to 10 days, 8 to 11 days, 8 to 12, 9 to 13, 10 to 14, 11 to 15, 12 to 16, 13 to 17, 14 to 18, 15 to 19, or 16 to 20 days.
  • the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 17 to 21 days, 18 to 22 days, 19 to 23 days, 20 to 24 days, 21 to 25, days, 22 to 26 days, 23 to 27 days, 24 to 28 days, 25 to 29 days, or 26 to 30 days.
  • the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention can be up to about 50 days.
  • the half-lives of antibodies and of compositions of the invention can be prolonged by methods known in the art. Such prolongation can in turn reduce the amount and/or frequency of dosing of the antibody compositions.
  • Antibodies with improved in vivo half-lives and methods for preparing them are disclosed in U.S. Patent No. 6,277,375; and International Publication Nos. WO 98/23289 and WO 97/3461.
  • the invention provides an article of manufacture including a container.
  • the container includes a composition containing a targeted binding agent or antibody as disclosed herein, and a package insert or label indicating that the composition can be used to treat cell adhesion, invasion, angiogenesis, and/or proliferation -related diseases, including, but not limited to, diseases characterised by the expression or overexpression of B7-H1.
  • the invention provides a kit for treating diseases involving the expression of B7-H1, comprising a targeted binding agent or antibody as disclosed herein, and instructions to administer the monoclonal antibodies to a subject in need of treatment.
  • the present invention provides formulation of proteins comprising a variant Fc region. That is, a non naturally occurring Fc region, for example an Fc region comprising one or more non naturally occurring amino acid residues. Also encompassed by the variant Fc regions of present invention are Fc regions which comprise amino acid deletions, additions and/or modifications.
  • the serum half-life of proteins comprising Fc regions may be increased by increasing the binding affinity of the Fc region for FcRn. In one embodiment, the Fc variant protein has enhanced serum half life relative to comparable molecule.
  • the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat.
  • the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat and at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 234, 235 and 331 , as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat.
  • an Fc variant of the invention comprises the 234F, 235F, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat.
  • an Fc variant of the invention comprises the 234F, 235 Y, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat.
  • an Fc variant of the invention comprises the 234F, 235E, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat.
  • the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat; at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, and 33 IS, as numbered by the EU index as set forth in Kabat, and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
  • the "OPT” and “TM” designations are synonymous and are used to describe antibodies of the invention engineered to introduce the three mutations; L234F and L235E in the hinge and P331S in the CH2 domain of the IgG molecule to eliminate its ability to trigger antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity (Oganesyan V. et al. (2008), Acta Cryst., D64: 700-704).
  • the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least a non naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat.
  • the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 234, 235 and 331, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat.
  • the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
  • the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat; and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
  • amino acid substitutions and/or deletions can be generated by mutagenesis methods, including, but not limited to, site-directed mutagenesis (Kunkel, Proc. Natl. Acad. Sci. USA 82:488-492 (1985) ), PCR mutagenesis (Higuchi, in “PCR Protocols: A Guide to Methods and Applications", Academic Press, San Diego, pp. 177-183 (1990)), and cassette mutagenesis (Wells et al, Gene 34:315-323 (1985)).
  • site-directed mutagenesis is performed by the overlap-extension PCR method (Higuchi, in "PCR Technology: Principles and Applications for DNA Amplification", Stockton Press, New York, pp. 61-70 (1989)).
  • the technique of overlap- extension PCR can also be used to introduce any desired mutation(s) into a target sequence (the starting DNA).
  • the first round of PCR in the overlap- extension method involves amplifying the target sequence with an outside primer (primer 1) and an internal mutagenesis primer (primer 3), and separately with a second outside primer (primer 4) and an internal primer (primer 2), yielding two PCR segments (segments A and B).
  • the internal mutagenesis primer (primer 3) is designed to contain mismatches to the target sequence specifying the desired mutation(s).
  • the products of the first round of PCR (segments A and B) are amplified by PCR using the two outside primers (primers 1 and 4).
  • the resulting full-length PCR segment (segment C) is digested with restriction enzymes and the resulting restriction fragment is cloned into an appropriate vector.
  • the starting DNA e.g., encoding an Fc fusion protein, an antibody or simply an Fc region
  • the primers are designed to reflect the desired amino acid substitution.
  • the glycosylation patterns of the antibodies provided herein are modified to enhance ADCC and CDC effector function. See Shields RL et al, (2002) JBC. 277:26733; Shinkawa T et al, (2003) JBC. 278:3466 and Okazaki A et al, (2004) J. Mol. Biol., 336: 1239.
  • an Fc variant protein comprises one or more engineered glycoforms, i.e., a carbohydrate composition that is covalently attached to the molecule comprising an Fc region.
  • Engineered glycoforms may be useful for a variety of purposes, including but not limited to enhancing or reducing effector function.
  • Engineered glycoforms may be generated by any method known to one skilled in the art, for example by using engineered or variant expression strains, by co-expression with one or more enzymes, for example DI N-acetylglucosaminyltransferase III (GnTIl l), by expressing a molecule comprising an Fc region in various organisms or cell lines from various organisms, or by modifying carbohydrate(s) after the molecule comprising Fc region has been expressed.
  • Methods for generating engineered glycoforms are known in the art, and include but are not limited to those described in Umana et al, 1999, Nat.
  • GlycoMAbTM glycosylation engineering technology GLYCART biotechnology AG, Zurich, Switzerland. See, e.g., WO 00061739; EA01229125; US 20030115614; Okazaki et al, 2004, JMB, 336: 1239-49.
  • glycosylation of the Fc region can be modified to increase or decrease effector function (see for examples, Umana et al, 1999, Nat. Biotechnol 17: 176-180; Davies et al, 2001, Biotechnol Bioeng 74:288-294; Shields et al, 2002, J Biol Chem 277:26733-26740; Shinkawa et al, 2003, J Biol Chem 278:3466-3473) U.S. Pat. No. 6,602,684; U.S. Ser. No. 10/277,370; U.S. Ser. No.
  • the Fc regions of the antibodies of the invention comprise altered glycosylation of amino acid residues.
  • the altered glycosylation of the amino acid residues results in lowered effector function.
  • the altered glycosylation of the amino acid residues results in increased effector function.
  • the Fc region has reduced fucosylation.
  • the Fc region is afucosylated (see for examples, U.S. Patent Application Publication No.2005/0226867).
  • Fig. 1 is a bar graph showing the effects of the anti-B7-Hl antibodies of the invention on
  • Fig. 2 is a bar graph showing enhancement of T-cell proliferation by anti-B7-Hl antibodies of the invention in DCMLR assay.
  • Fig. 3 is a bar graph showing IFN- ⁇ release by anti-B7-Hl antibodies of the invention in DCMLR assay.
  • Fig. 4 is a graph showing 95% confidence interval for anti-B7-Hl IC50 by anti-B7-Hl antibodies of the invention in the human PD1 /human B7-H1 ligand inhibition assay to evaluate the impact of IgG class switching and germlining on antibody activity.
  • Fig. 5 is a line graph showing the results from an ELISA assay that was performed to evaluate anti-B7-Hl antibodies of the invention cross-reactivity to co-modulatory antigens.
  • Fig. 6 is a bar graph showing the effects of anti-B7-Hl antibodies of the invention in the in-vitro Tet-recall assay.
  • Fig. 7 is a bar graph showing the results form testing agonism activity of anti-B7-Hl antibodies of the invention using the Tet-recall assay.
  • Fig. 8A/B/C are line graphs showing the effect of anti-B7-Hl antibodies of the invention on HPAC cells in a mouse xenograft model.
  • Fig. 9A/B/C are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
  • Fig. 10A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on HPAC cells in a mouse xenograft model.
  • Fig. 11 is a line graph showing the effect of anti-B7-Hl antibodies of the invention on
  • FIG. 12A/B/C/D are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
  • Fig. 13A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model with and without the presence of T cells.
  • Fig. 14A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model with and without the presence of T cells.
  • Fig. 15 is a line graph showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
  • Standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See for example, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001)), which is incorporated herein by reference.
  • An antagonist or inhibitor may be a polypeptide, nucleic acid, carbohydrate, lipid, small molecular weight compound, an oligonucleotide, an oligopeptide, RNA interference (RNAi), antisense, a recombinant protein, an antibody, or fragments thereof or conjugates or fusion proteins thereof.
  • RNAi RNA interference
  • antisense see Opalinska JB, Gewirtz AM. (Sci STKE. 2003 Oct 28;2003 (206):pe47.)
  • a compound refers to any small molecular weight compound with a molecular weight of less than about 2000 Daltons.
  • B7-H1 refers to the human B7-H, B7H1, B7-H1, B7 homolog 1, CD274 antigen, PDCD1L1, PDCD1LG1, PDCD1 ligand 1, PDL1, PD-L1, Programmed cell death 1 ligand 1 precursor, or Programmed death ligand 1.
  • neutralising when referring to a targeted binding agent, such as an antibody, relates to the ability of said agent to eliminate, reduce, or significantly reduce, the activity of a target antigen.
  • a “neutralising” anti-B7-Hl antibody of the invention is capable of eliminating or significantly reducing the activity of B7-H1.
  • a neutralising, antagonising or inhibiting antibody that specifically binds B7-H1 may, for example, act by blocking the binding of B7-H1 to its cognate ligands.
  • a neutralising antibody against B7- HI inhibits B7-H1 mediated repression of T-cell immunity.
  • a neutralising, antagonising or inhibiting antibody that specifically binds B7-H1 may, for example, act by inhibiting binding of B7-H1 to PD-1 and/or to B7-1.
  • “Inhibiting the biological activity of B7-H1” encompasses an inhibition of B7-H1 activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%), at least 80%>, at least 85%>, at least 90%>, or at least 95%> in comparison with the biological activity in the absence of a targeted binding agent or antibody of the invention.
  • polypeptide is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence.
  • native protein, fragments, and analogs are species of the polypeptide genus.
  • Preferred polypeptides in accordance with the invention comprise the human heavy chain immunoglobulin molecules and the human kappa light chain immunoglobulin molecules, as well as antibody molecules formed by combinations comprising the heavy chain immunoglobulin molecules with light chain immunoglobulin molecules, such as the kappa or lambda light chain immunoglobulin molecules, and vice versa, as well as fragments and analogs thereof.
  • Preferred polypeptides in accordance with the invention may also comprise solely the human heavy chain immunoglobulin molecules or fragments thereof.
  • naturally occurring refers to the fact that an object can be found in nature.
  • a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory or otherwise is naturally occurring.
  • control sequence refers to polynucleotide sequences that are necessary either to effect or to affect the expression and processing of coding sequences to which they are connected. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences may include promoters, enhancers, introns, transcription termination sequences, polyadenylation signal sequences, and 5' and '3 untranslated regions.
  • control sequences is intended to include, at a minimum, all components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
  • polynucleotide as referred to herein means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide, or RNA-DNA hetero-duplexes.
  • the term includes single and double stranded forms of DNA.
  • oligonucleotide includes naturally occurring, and modified nucleotides linked together by naturally occurring, and non naturally occurring linkages. Oligonucleotides are a polynucleotide subset generally comprising a length of 200 bases or fewer. Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in length. Oligonucleotides are usually single stranded, e.g. for probes; although oligonucleotides may be double stranded, e.g. for use in the construction of a gene mutant. Oligonucleotides can be either sense or antisense oligonucleotides.
  • nucleotides includes deoxyribonucleotides and ribonucleotides.
  • modified nucleotides includes nucleotides with modified or substituted sugar groups and the like.
  • oligonucleotide linkages includes oligonucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res.
  • oligonucleotide can include a label for detection, if desired.
  • selective hybridise means to detectably and specifically bind.
  • Polynucleotides, oligonucleotides and fragments thereof selectively hybridise to nucleic acid strands under hybridisation and wash conditions that minimise appreciable amounts of detectable binding to nonspecific nucleic acids.
  • High stringency conditions can be used to achieve selective hybridisation conditions as known in the art and discussed herein.
  • the nucleic acid sequence homology between the polynucleotides, oligonucleotides, or antibody fragments and a nucleic acid sequence of interest will be at least 80%, and more typically with preferably increasing homologies of at least 85%, 90%, 95%, 99%, and 100%.
  • Stringent hybridization conditions include, but are not limited to, hybridization to filter- bound DNA in 6X sodium chloride/sodium citrate (SSC) (0.9 M NaCl/90 mM NaCitrate, pH 7.0) at about 45°C followed by one or more washes in 0.2X SSC/0.1% SDS at about 50-65°C, highly stringent conditions such as hybridization to filter-bound DNA in 6X SSC at about 45°C followed by one or more washes in 0.1X SSC/0.2%o SDS at about 60°C, or any other stringent hybridization conditions known to those skilled in the art (see, for example, Ausubel, F.M. et al., eds. 1989 Current Protocols in Molecular Biology, vol. 1, Green Publishing Associates, Inc. and John Wiley and Sons, Inc., NY at pages 6.3.1 to 6.3.6 and 2.10.3).
  • SSC sodium chloride/sodium citrate
  • Two amino acid sequences are "homologous" if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximising matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively and preferably, two protein sequences (or polypeptide sequences derived from them of at least about 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater.
  • the two sequences or parts thereof are more preferably homologous if their amino acids are greater than or equal to 50% identical when optimally aligned using the ALIGN program. It should be appreciated that there can be differing regions of homology within two orthologous sequences. For example, the functional sites of mouse and human orthologues may have a higher degree of homology than non-functional regions.
  • a polynucleotide sequence is homologous (i.e., is identical, not strictly evolutionarily related) to all or a portion of a reference polynucleotide sequence, or that a polypeptide sequence is identical to a reference polypeptide sequence.
  • the term “complementary to” is used herein to mean that the complementary sequence is homologous to all or a portion of a reference polynucleotide sequence.
  • the nucleotide sequence "TATAC” corresponds to a reference sequence “TATAC” and is complementary to a reference sequence "GTATA”.
  • sequence identity means that two polynucleotide or amino acid sequences are identical (i.e., on a nucleotide-by-nucleotide or residue-by-residue basis) over the comparison window.
  • percentage of sequence identity is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.
  • substantially identical denotes a characteristic of a polynucleotide or amino acid sequence, wherein the polynucleotide or amino acid comprises a sequence that has at least 85 percent sequence identity, preferably at least 90 to 95 percent sequence identity, more preferably at least 99 percent sequence identity, as compared to a reference sequence over a comparison window of at least 18 nucleotide (6 amino acid) positions, frequently over a window of at least 24-48 nucleotide (8-16 amino acid) positions, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the comparison window.
  • the reference sequence may be a subset of a larger sequence .
  • the twenty conventional amino acids and their abbreviations follow conventional usage. See Immunology - A Synthesis (2 nd Edition, E.S. Golub and D.R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference.
  • Stereoisomers e.g., D-amino acids
  • unnatural amino acids such as ⁇ -, ⁇ -disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for polypeptides of the present invention.
  • Examples of unconventional amino acids include: 4- hydroxyproline, ⁇ -carboxyglutamate, ⁇ - ⁇ , ⁇ , ⁇ -trimethyllysine, ⁇ - ⁇ -acetyllysine, O- phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ⁇ - ⁇ - methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).
  • the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.
  • the left-hand end of single-stranded polynucleotide sequences is the 5 ' end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5' direction.
  • the direction of 5' to 3' addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA and which are 5 ' to the 5 ' end of the RNA transcript are referred to as "upstream sequences"; sequence regions on the DNA strand having the same sequence as the RNA and which are 3' to the 3' end of the RNA transcript are referred to as "downstream sequences".
  • the term "substantial identity” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity, and most preferably at least 99 percent sequence identity.
  • residue positions that are not identical differ by conservative amino acid substitutions.
  • Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains.
  • a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur- containing side chains is cysteine and methionine.
  • Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic-aspartic, and asparagine-glutamine.
  • minor variations in the amino acid sequences of antibodies or immunoglobulin molecules are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence maintain at least 75%, more preferably at least 80%>, 90%, 95%, and most preferably 99% sequence identity to the antibodies or immunoglobulin molecules described herein.
  • conservative amino acid replacements are contemplated. Conservative replacements are those that take place within a family of amino acids that have related side chains.
  • More preferred families are: serine and threonine are an aliphatic-hydroxy family; asparagine and glutamine are an amide-containing family; alanine, valine, leucine and isoleucine are an aliphatic family; and phenylalanine, tryptophan, and tyrosine are an aromatic family.
  • Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases.
  • computerised comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. Bowie et al. Science 253: 164 (1991).
  • Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. These residues are deamidated under neutral or basic conditions. The deamidated form of these residues falls within the scope of this invention.
  • cysteine residues in proteins are either engaged in cysteine-cysteine disulfide bonds or sterically protected from the disulfide bond formation when they are a part of folded protein region.
  • Disulfide bond formation in proteins is a complex process, which is determined by the redox potential of the environment and specialized thiol-disulfide exchanging enzymes (Creighton, Methods Enzymol. 107, 305-329, 1984; Houee-Levin, Methods Enzymol. 353, 35- 44,2002).
  • cysteine residue When a cysteine residue does not have a pair in protein structure and is not sterically protected by folding, it can form a disulfide bond with a free cysteine from solution in a process known as disulfide shuffling. In another process known as disulfide scrambling, free cysteines may also interfere with naturally occurring disulfide bonds (such as those present in antibody structures) and lead to low binding, low biological activity and/or low stability.
  • Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogs.
  • Analogs can include various muteins of a sequence other than the naturally occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts.
  • a conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterises the parent sequence).
  • Examples of art-recognised polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et at. Nature 354: 105 (1991), which are each incorporated herein by reference. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds.
  • CDR region or “CDR” is intended to indicate the hypervariable regions of the heavy and light chains of an antibody which confer the antigen-binding specificity to the antibody.
  • CDRs may be defined according to the Kabat system (Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th Edition. US Department of Health and Human Services, Public Service, NIH, Washington), and later editions.
  • An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs.
  • CDR or CDRs is used here in order to indicate, according to the case, one of these regions or several, or even the whole, of these regions which contain the majority of the amino acid residues responsible for the binding by affinity of the antibody for the antigen or the epitope which it recognises.
  • the third CDR of the heavy chain (HCDR3) has a greater size variability (greater diversity essentially due to the mechanisms of arrangement of the genes which give rise to it). It may be as short as 2 amino acids although the longest size known is 26. CDR length may also vary according to the length that can be accommodated by the particular underlying framework. Functionally, HCDR3 plays a role in part in the determination of the specificity of the antibody (Segal et al, PNAS, 71 :4298-4302, 1974, Amit et al, Science, 233:747-753, 1986, Chothia et al, J. Mol.
  • a "set of CDRs" referred to herein comprises CDR1, CDR2 and CDR3.
  • a set of HCDRs refers to HCDR1, HCDR2 and HCDR3
  • a set of LCDRs refers to LCDR1, LCDR2 and LCDR3.
  • Variants of the VH and VL domains and CDRs of the present invention including those for which amino acid sequences are set out herein, and which can be employed in targeting binding agents and antibodies for B7-H1 can be obtained by means of methods of sequence alteration or mutation and screening for antigen targeting with desired characteristics.
  • desired characteristics include but are not limited to: increased binding affinity for antigen relative to known antibodies which are specific for the antigen; increased neutralisation of an antigen activity relative to known antibodies which are specific for the antigen if the activity is known; specified competitive ability with a known antibody or ligand to the antigen at a specific molar ratio; ability to immunoprecipitate ligand-receptor complex; ability to bind to a specified epitope; linear epitope, e.g.
  • peptide sequence identified using peptide-binding scan e.g. using peptides screened in linear and/or constrained conformation; conformational epitope, formed by non-continuous residues; ability to modulate a new biological activity of B7-H1, or downstream molecule; ability to bind and/or neutralise B7-H1 and/or for any other desired property.
  • the techniques required to make substitutions within amino acid sequences of CDRs, antibody VH or VL domains and antigen binding sites are available in the art. Variants of antibody molecules disclosed herein may be produced and used in the present invention. Following the lead of computational chemistry in applying multivariate data analysis techniques to the structure/property-activity relationships (Wold, et al.
  • the properties of antibodies can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of antibody sequence, functional and three-dimensional structures and these properties can be considered singly and in combination.
  • An antibody antigen-binding site composed of a VH domain and a VL domain is typically formed by six loops of polypeptide: three from the light chain variable domain (VL) and three from the heavy chain variable domain (VH).
  • VL light chain variable domain
  • VH heavy chain variable domain
  • Analysis of antibodies of known atomic structure has elucidated relationships between the sequence and three-dimensional structure of antibody combining sites. These relationships imply that, except for the third region (loop) in VH domains, binding site loops have one of a small number of main-chain conformations: canonical structures.
  • the canonical structure formed in a particular loop has been shown to be determined by its size and the presence of certain residues at key sites in both the loop and in framework regions.
  • sequence-structure relationship can be used for prediction of those residues in an antibody of known sequence, but of an unknown three-dimensional structure, which are important in maintaining the three-dimensional structure of its CDR loops and hence maintain binding specificity. These predictions can be backed up by comparison of the predictions to the output from lead optimisation experiments.
  • a model can be created of the antibody molecule using any freely available or commercial package, such as WAM.
  • a protein visualisation and analysis software package such as Insight II (Accelrys, Inc.) or Deep View may then be used to evaluate possible substitutions at each position in the CDR. This information may then be used to make substitutions likely to have a minimal or beneficial effect on activity or confer other desirable properties.
  • polypeptide fragment refers to a polypeptide that has an amino- terminal and/or carboxy-terminal deletion, but where the remaining amino acid sequence is identical to the corresponding positions in the naturally occurring sequence deduced, for example, from a full-length cDNA sequence. Fragments typically are at least 5, 6, 8 or 10 amino acids long, preferably at least 14 amino acids long, more preferably at least 20 amino acids long, usually at least 50 amino acids long, and even more preferably at least 70 amino acids long.
  • analog refers to polypeptides which are comprised of a segment of at least 25 amino acids that has substantial identity to a portion of a deduced amino acid sequence and which has at least one of the following properties: (1) specific binding to B7-H1, under suitable binding conditions, (2) ability to block appropriate B7-H1 -protein binding, or (3) ability to inhibit B7-H1 activity.
  • polypeptide analogs comprise a conservative amino acid substitution (or addition or deletion) with respect to the naturally occurring sequence.
  • Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally occurring polypeptide.
  • Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics”. Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS p.392 (1985); and Evans et al. J. Med. Chem. 30: 1229 (1987), which are incorporated herein by reference. Such compounds are often developed with the aid of computerised molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent therapeutic or prophylactic effect.
  • a paradigm polypeptide i.e., a polypeptide that has a biochemical property or pharmacological activity
  • Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type may be used to generate more stable peptides.
  • constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo and Gierasch Ann. Rev. Biochem. 61 :387 (1992), incorporated herein by reference); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclise the peptide.
  • antibody and “antibodies” (immunoglobulins) may be an oligoclonal antibody, a polyclonal antibody, a monoclonal antibody (including full-length monoclonal antibodies), a camelised antibody, a chimeric antibody, a CDR-grafted antibody, a multi-specific antibody, a bi-specific antibody, a catalytic antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an anti-idiotypic antibody and antibodies that can be labeled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques.
  • An antibody may be from any species.
  • An antibody comprises a polypeptide or group of polypeptides that are comprised of at least one binding domain that is formed from the folding of polypeptide chains having three- dimensional binding spaces with internal surface shapes and charge distributions complementary to the features of an antigenic determinant of an antigen.
  • An antibody typically has a tetrameric form, comprising two identical pairs of polypeptide chains, each pair having one "light” and one "heavy” chain. The variable regions of each light/heavy chain pair form an antibody binding site.
  • Native antibodies are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains.
  • Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes.
  • Each heavy and light chain also has regularly spaced intrachain disulfide bridges.
  • Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
  • Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
  • Light chains are classified as either lambda chains or kappa chains based on the amino acid sequence of the light chain constant region.
  • variable domain of a kappa light chain may also be denoted herein as VK.
  • variable region may also be used to describe the variable domain of a heavy chain or light chain. Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains.
  • the variable regions of each light/heavy chain pair form an antibody binding site.
  • Such antibodies may be derived from any mammal, including, but not limited to, humans, monkeys, pigs, horses, rabbits, dogs, cats, mice, etc.
  • antibody or “antibodies” includes binding fragments of the antibodies of the invention, exemplary fragments include single-chain Fvs (scFv), single-chain antibodies, single domain antibodies, domain antibodies, Fv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-stabilised variable region (dsFv), dimeric variable region (Diabody), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), intrabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope-binding fragments of any of the above.
  • scFv single-chain Fvs
  • dsFv disulfide-stabilised variable region
  • Diabody dimeric variable region
  • anti-Id antibodies including, e.g., anti-Id antibodies to antibodies of the invention
  • intrabodies linear antibodies, single-chain antibody molecules and multi
  • antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site.
  • Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass.
  • Digestion of antibodies with the enzyme, papain results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallise.
  • Digestion of antibodies with the enzyme, pepsin results in the a F(ab') 2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites.
  • the F(ab') 2 fragment has the ability to crosslink antigen.
  • Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • Fab when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CHI domain of the heavy chain.
  • dAb when used herein refers to a fragment of an antibody that is the smallest functional binding unit of a human antibodies.
  • a “dAb” is a single domain antibody and comprises either the variable domain of an antibody heavy chain (VH domain) or the variable domain of an antibody light chain (VL domain).
  • VH domain variable domain of an antibody heavy chain
  • VL domain variable domain of an antibody light chain
  • Each dAb contains three of the six naturally occurring CDRs (Ward et al., Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature 341, 544-546 (1989); Holt, et al., Domain antibodies: protein for therapy, Trends Biotechnol. 21, 484-49 (2003)). With molecular weights ranging from 11 to 15 kDa, they are four times smaller than a fragment antigen binding (Fab)2 and half the size of a single chain Fv (scFv) molecule.
  • Fab fragment antigen binding
  • “Camelid” when used herein refers to antibody molecules are composed of heavy-chain dimers which are devoid of light chains, but nevertheless have an extensive antigen-binding repertoire (Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R (1993) Naturally occurring antibodies devoid of light chains. Nature 363:446-448).
  • the term "diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V R ) connected to a light chain variable domain (V L ) in the same polypeptide chain (V H -V L ).
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl Acad. Sci. USA, 90:6444-6448 (1993).
  • binding fragments are (Ward, E.S. et al., (1989) Nature 341, 544-546) the Fab fragment consisting of VL, VH, CL and CHI domains; (McCafferty et al (1990) Nature, 348, 552-554) the Fd fragment consisting of the VH and CHI domains; (Holt et al (2003) Trends in Biotechnology 21, 484-490) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward, E.S.
  • Fv, scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains (Reiter, Y. et al, Nature Biotech, 14, 1239-1245, 1996).
  • Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu, S. et al, (1996) Cancer Res., 56, 3055- 3061).
  • binding fragments are Fab', which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CHI domain, including one or more cysteines from the antibody hinge region, and Fab'-SH, which is a Fab' fragment in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are responsible for the binding specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed through the variable domains of antibodies. It is concentrated in segments called Complementarity Determining Regions (CDRs) both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework regions (FR).
  • CDRs Complementarity Determining Regions
  • FR framework regions
  • the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a ⁇ -sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the ⁇ -sheet structure.
  • the CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)).
  • the constant domains are generally not involved directly in antigen binding, but may influence antigen binding affinity and may exhibit various effector functions, such as participation of the antibody in ADCC, CDC, and/or apoptosis.
  • hypervariable region when used herein refers to the amino acid residues of an antibody which are associated with its binding to antigen.
  • the hypervariable regions encompass the amino acid residues of the "complementarity determining regions" or "CDRs” (e.g., residues 24-34 (LI), 50-56 (L2) and 89-97 (L3) of the light chain variable domain and residues 31-35 (HI), 50-65 (H2) and 95-102 (H3) of the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.
  • CDRs complementarity determining regions
  • target binding agent refers to an agent, for example an antibody, or binding fragment thereof, that preferentially binds to a target site.
  • the targeted binding agent is specific for only one target site. In other embodiments, the targeted binding agent is specific for more than one target site.
  • the targeted binding agent may be a monoclonal antibody and the target site may be an epitope.
  • a targeted binding agent may comprise at least one antigen binding domain (e.g. a CDR) of an antibody, wherein said domain is fused or contained within a heterologous protein scaffold, e.g. a non-antibody protein scaffold.
  • Binding fragments of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab') 2 , Fv, dAb and single-chain antibodies. An antibody other than a "bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. An antibody substantially inhibits adhesion of a receptor to a counter-receptor when an excess of antibody reduces the quantity of receptor bound to counter-receptor by at least about 20%, 40%>, 60%> or 80%o, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
  • epitopic determinants includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor.
  • Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and may, but not always, have specific three-dimensional structural characteristics, as well as specific charge characteristics.
  • An antibody is said to specifically bind an antigen when the dissociation constant is ⁇ 1 ⁇ , preferably ⁇ 100 nM and most preferably ⁇ 10 nM.
  • agent is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
  • B7-H1 polypeptide refers to a portion of aB7-Hl polypeptide that has a biological or an immunological activity of a native B7-H1 polypeptide.
  • Biological when used herein refers to a biological function that results from the activity of the native B7-H1 polypeptide.
  • a preferred B7-H1 biological activity includes, for example, B7-H1 induced cell proliferation, cell adhesion and invasion.
  • mammal when used herein refers to any animal that is considered a mammal. Preferably, the mammal is human.
  • Animal when used herein encompasses animals considered a mammal. Preferably the animal is human.
  • patient includes human and veterinary subjects.
  • mAb refers to monoclonal antibody.
  • Liposome when used herein refers to a small vesicle that may be useful for delivery of drugs that may include the B7-H1 polypeptide of the invention or antibodies to such a B7-H1 polypeptide to a mammal.
  • Label refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label chemiluminescent labeled or a biotinyl group.
  • Radioisotopes or radionuclides may include 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, m In, 125 1, 131 I, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, ⁇ -galactosidase, luciferase, alkaline phosphatase.
  • Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH”), alpha-D-galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes; additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein”), dansyl, umbelliferone, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, and fiuorescamine; fluorophores such as lanthanide cryptates and chelates e.g.
  • enzymes such as glucose-6-phosphate dehydrogenase (“G6PDH”), alpha-D-galactosidase, glucose oxydase,
  • chemoluminescent labels or chemiluminescers such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5-bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof, sap
  • pharmaceutical agent or drug refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.
  • Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)), (incorporated herein by reference).
  • substantially pure means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present.
  • a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, more preferably more than about 85%, 90%, 95%), and 99%.
  • the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
  • Antibody-dependent cell-mediated cytotoxicity and “ADCC” refer to a cell-mediated reaction in which non-specific cytotoxic cells that express Ig Fc receptors (FcRs) (e.g. Natural Killer (NK) cells, monocytes, neutrophils, and macrophages) recognise bound antibody on a target cell and subsequently cause lysis of the target cell.
  • FcRs Ig Fc receptors
  • NK cells Natural Killer (NK) cells, monocytes, neutrophils, and macrophages
  • FcRs expression on hematopoietic cells is summarised in Table 9 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
  • ADCC activity of a molecule of interest can be assessed in vitro, such as that described in U.S. Patent No. 5,500,362, or 5,821,337.
  • useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • PBMC peripheral blood mononuclear cells
  • NK Natural Killer
  • ADCC activity of the molecule of interest can be assessed in vivo, e.g. , in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1988).
  • “Complement dependent cytotoxicity” and “CDC” refer to the mechanism by which antibodies carry out their cell-killing function. It is initiated by the binding of Clq, a constituent of the first component of complement, to the Fc domain of Igs, IgG or IgM, which are in complex with antigen (Hughs- Jones, N.C., and B. Gardner. 1979. Mol. Immunol. 16:697). Clq is a large, structurally complex glycoprotein of -410 kDa present in human serum at a concentration of 70 ⁇ (Cooper, N.R. 1985. Adv. Immunol. 37: 151). Together with two serine proteases, Clr and Cls, Clq forms the complex CI, the first component of complement.
  • antibody half-life means a pharmacokinetic property of an antibody that is a measure of the mean survival time of antibody molecules following their administration.
  • Antibody half-life can be expressed as the time required to eliminate 50 percent of a known quantity of immunoglobulin from the patient's body or a specific compartment thereof, for example, as measured in serum or plasma, i.e., circulating half-life, or in other tissues.
  • Half-life may vary from one immunoglobulin or class of immunoglobulin to another. In general, an increase in antibody half-life results in an increase in mean residence time (MRT) in circulation for the antibody administered.
  • MRT mean residence time
  • isotype refers to the classification of an antibody's heavy or light chain constant region.
  • the constant domains of antibodies are not involved in binding to antigen, but exhibit various effector functions.
  • a given human antibody or immunoglobulin can be assigned to one of five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM.
  • IgA, IgD, IgE, IgG, and IgM Several of these classes may be further divided into subclasses (isotypes), e.g., IgGl (gamma 1), IgG2 (gamma 2), IgG3 (gamma 3), and IgG4 (gamma 4), and IgAl and IgA2.
  • the heavy chain constant regions that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the structures and three-dimensional configurations of different classes of immunoglobulins are well- known.
  • human immunoglobulin classes only human IgGl, IgG2, IgG3, IgG4, and IgM are known to activate complement.
  • Human IgGl, IgG2, IgG3, and IgG4 are known to bind Fc gamma receptors, which mediate various effector functions including ADCC.
  • Human light chain constant regions may be classified into two major classes, kappa and lambda.
  • the isotype of an antibody that specifically binds B7-H1 can be switched, for example to take advantage of a biological property of a different isotype.
  • the antibodies in some circumstances it can be desirable in connection with the generation of antibodies as therapeutic antibodies against B7-H1 that the antibodies be capable of fixing complement and participating in complement-dependent cytotoxicity (CDC).
  • CDC complement-dependent cytotoxicity
  • isotypes of antibodies that are capable of the same, including, without limitation, the following: murine IgM, murine IgG2a, murine IgG2b, murine IgG3, human IgM, human IgA, human IgGl, and human IgG3.
  • antibodies can be desirable in connection with the generation of antibodies as therapeutic antibodies against B7-H1 that the antibodies be capable of binding Fc receptors on effector cells and participating in antibody-dependent cytotoxicity (ADCC).
  • ADCC antibody-dependent cytotoxicity
  • isotypes of antibodies that are capable of the same, including, without limitation, the following: murine IgG2a, murine IgG2b, murine IgG3, human IgGl, and human IgG3.
  • antibodies that are generated need not initially possess such an isotype but, rather, the antibody as generated can possess any isotype and the antibody can be isotype switched thereafter using conventional techniques that are well known in the art. Such techniques include the use of direct recombinant techniques (see e.g., U.S. Patent No. 4,816,397), cell-cell fusion techniques (see e.g., U.S. Patent Nos. 5,916,771 and 6,207,418), among others.
  • the anti- B7-H1 antibodies discussed herein are fully human antibodies. If an antibody possessed desired binding to B7-H1, it could be readily isotype switched to generate a human IgM, human IgGl, or human IgG3 isotype, while still possessing the same variable region (which defines the antibody's specificity and some of its affinity). Such molecule would then be capable of fixing complement and participating in CDC and/or be capable of binding to Fc receptors on effector cells and participating in ADCC.
  • Blood assays use unfractionated blood as a source of natural effectors. Blood contains complement in the plasma, together with FcR-expressing cellular effectors, such as polymorphonuclear cells (PMNs) and mononuclear cells (MNCs). Thus, whole blood assays allow simultaneous evaluation of the synergy of both ADCC and CDC effector mechanisms in vitro.
  • PMNs polymorphonuclear cells
  • MNCs mononuclear cells
  • a “therapeutically effective” amount as used herein is an amount that provides some improvement or benefit to the subject. Stated in another way, a “therapeutically effective” amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom. Clinical symptoms associated with the disorders that can be treated by the methods of the invention are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
  • Exemplary cancers in humans include a bladder tumour, breast tumour, prostate tumour, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and CNS cancer (e.g., glioma tumour), cervical cancer, choriocarcinoma, colon and rectum cancer, connective tissue cancer, cancer of the digestive system; endometrial cancer, esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g.
  • lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma, neuroblastoma, oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer, retinoblastoma; rhabdomyosarcoma; rectal cancer, renal cancer, cancer of the respiratory system; sarcoma, skin cancer; stomach cancer, testicular cancer, thyroid cancer; uterine cancer, cancer of the urinary system, as well as other carcinomas and sarcomas.
  • Exemplary chronic infections in humans include HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV).
  • HIV hepatitis B virus
  • HCV hepatitis C virus
  • the basic antibody structural unit is known to comprise a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy” chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function.
  • Human light chains are classified as kappa and lambda light chains.
  • Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgA, and IgE, respectively.
  • variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D” region of about 10 more amino acids.
  • J Fundamental Immunology Ch. 7
  • D variable region of about 10 more amino acids.
  • an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are the same.
  • the chains all exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called CDRs.
  • the CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989).
  • a bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites.
  • Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann Clin. Exp. Immunol. 79: 315-321 (1990), Kostelny et al. J. Immunol. 148: 1547-1553 (1992). Bispecific antibodies do not exist in the form of fragments having a single binding site (e.g., Fab, Fab', and Fv).
  • a VH domain is paired with a VL domain to provide an antibody antigen- binding site, although a VH or VL domain alone may be used to bind antigen.
  • the VH domain (see Table 9) may be paired with the VL domain (see Table 13), so that an antibody antigen- binding site is formed comprising both the VH and VL domains
  • Human antibodies avoid some of the problems associated with antibodies that possess murine or rat variable and/or constant regions.
  • the presence of such murine or rat derived proteins can lead to the rapid clearance of the antibodies or can lead to the generation of an immune response against the antibody by a patient.
  • fully human antibodies can be generated through the introduction of functional human antibody loci into a rodent, other mammal or animal so that the rodent, other mammal or animal produces fully human antibodies.
  • XenoMouse ® strains of mice that have been engineered to contain up to but less than 1000 kb-sised germline configured fragments of the human heavy chain locus and kappa light chain locus. See Mendez et al. Nature Genetics 15: 146-156 (1997) and Green and Jakobovits J. Exp. Med. 188:483-495 (1998).
  • the XenoMouse ® strains are available from Amgen, Inc. (Fremont, California, U.S.A).
  • mice are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies.
  • Technologies utilised for achieving the same are disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15:146-156 (1997), the disclosure of which is hereby incorporated by reference.
  • minilocus In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus.
  • Kirin has also demonstrated the generation of human antibodies from mice in which, through microcell fusion, large pieces of chromosomes, or entire chromosomes, have been introduced. See European Patent Application Nos. 773 288 and 843 961, the disclosures of which are hereby incorporated by reference. Additionally, KMTM- mice, which are the result of cross-breeding of Kirin's Tc mice with Medarex's minilocus (Humab) mice have been generated. These mice possess the human IgH transchromosome of the Kirin mice and the kappa chain transgene of the Genpharm mice (Ishida et al, Cloning Stem Cells, (2002) 4:91-102).
  • Human antibodies can also be derived by in vitro methods. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display, and the like.
  • mice were prepared through the utilization of the XenoMouse ® technology, as described below. Such mice are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilised for achieving the same are disclosed in the patents, applications, and references disclosed in the background section herein. In particular, however, a preferred embodiment of transgenic production of mice and antibodies therefrom is disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15: 146-156 (1997), the disclosure of which is hereby incorporated by reference.
  • XenoMouse ® lines of mice are immunised with an antigen of interest (e.g. B7-H1), lymphatic cells (such as B-cells) are recovered from the hyper- immunised mice, and the recovered lymphocytes are fused with a myeloid-type cell line to prepare immortal hybridoma cell lines.
  • B7-H1 an antigen of interest
  • lymphatic cells such as B-cells
  • myeloid-type cell line to prepare immortal hybridoma cell lines.
  • These hybridoma cell lines are screened and selected to identify hybridoma cell lines that produced antibodies specific to the antigen of interest.
  • Provided herein are methods for the production of multiple hybridoma cell lines that produce antibodies specific to B7-H1.
  • characterisation of the antibodies produced by such cell lines including nucleotide and amino acid sequence analyses of the heavy and light chains of such antibodies.
  • B cells can be directly assayed.
  • CD 19+ B cells can be isolated from hyperimmune XenoMouse® mice and allowed to proliferate and differentiate into antibody-secreting plasma cells.
  • Antibodies from the cell supernatants are then screened by ELISA for reactivity against the B7-H1 immunogen.
  • the supernatants might also be screened for immunoreactivity against fragments of B7-H1 to further map the different antibodies for binding to domains of functional interest on B7-H1.
  • the antibodies may also be screened other related human proteins and against the rat, the mouse, and non-human primate, such as Cynomolgus monkey, orthologues of B7-H1, the last to determine species cross-reactivity.
  • B cells from wells containing antibodies of interest may be immortalised by various methods including fusion to make hybridomas either from individual or from pooled wells, or by infection with EBV or transfection by known immortalising genes and then plating in suitable medium.
  • single plasma cells secreting antibodies with the desired specificities are then isolated using a B7-H1 -specific hemolytic plaque assay (see for example Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48 (1996)).
  • Cells targeted for lysis are preferably sheep red blood cells (SRBCs) coated with the B7-H1 antigen.
  • SRBCs sheep red blood cells coated with the B7-H1 antigen.
  • the single antigen-specific plasma cell in the center of the plaque can be isolated and the genetic information that encodes the specificity of the antibody is isolated from the single plasma cell.
  • RT-PCR reverse-transcription followed by PCR
  • Such cloned DNA can then be further inserted into a suitable expression vector, preferably a vector cassette such as a pcDNA, more preferably such a pcDNA vector containing the constant domains of immunglobulin heavy and light chain.
  • a suitable expression vector preferably a vector cassette such as a pcDNA, more preferably such a pcDNA vector containing the constant domains of immunglobulin heavy and light chain.
  • the generated vector can then be transfected into host cells, e.g., HEK293 cells, CHO cells, and cultured in conventional nutrient media modified as appropriate for inducing transcription, selecting transformants, or amplifying the genes encoding the desired sequences.
  • antibodies as described herein can be expressed in cell lines other than hybridoma cell lines. Sequences encoding particular antibodies can be used to transform a suitable mammalian host cell. Transformation can be by any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus (or into a viral vector) and transducing a host cell with the virus (or vector) or by transfection procedures known in the art, as exemplified by U.S. Patent Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents are hereby incorporated herein by reference). The transformation procedure used depends upon the host to be transformed.
  • Methods for introducing heterologous polynucleotides into mammalian cells include dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.
  • Mammalian cell lines available as hosts for expression are well known in the art and include many immortalised cell lines available from the NCIMB, including but not limited to Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), human epithelial kidney 293 cells (Hek293), and a number of other cell lines. Cell lines of particular preference are selected through determining which cell lines have high expression levels and produce antibodies with constitutive B7-H1 binding properties.
  • CHO Chinese hamster ovary
  • HeLa cells HeLa cells
  • BHK baby hamster kidney
  • COS monkey kidney cells
  • Hep G2 human hepatocellular carcinoma cells
  • Hek293 human epithelial kidney 293 cells
  • a myeloma, CHO cell or other cell line is prepared that possesses a heavy chain with any desired isotype and another myeloma, CHO cell or other cell line is prepared that possesses the light chain.
  • Such cells can, thereafter, be fused and a cell line expressing an intact antibody can be isolated.
  • antibody candidates are generated that meet desired "structural" attributes as discussed above, they can generally be provided with at least certain of the desired "functional” attributes through isotype switching.
  • a myeloma, CHO cell or other cell line is prepared that possesses a heavy chain with any desired isotype and another myeloma, CHO cell or other cell line is prepared that possesses the light chain.
  • Such cells can, thereafter, be fused and a cell line expressing an intact antibody can be isolated.
  • antibody candidates are generated that meet desired "structural" attributes as discussed above, they can generally be provided with at least certain of the desired "functional” attributes through isotype switching.
  • Embodiments of the invention include the antibodies listed below in Table 1. This table reports the identification number of each antibody, along with the SEQ ID number of the variable domain of the corresponding heavy chain and light chain genes and polypeptides, respectively. Each antibody sequence has been given an identification number.
  • Embodiments of the invention include sterile pharmaceutical formulations of anti-B7-Hl antibodies that are useful as treatments for diseases. Such formulations would inhibit the binding of B7-H1 to one or more of its cognate ligands, thereby treating pathological conditions where, for example, serum or tissue B7-H1 is abnormally elevated.
  • Antibodies of the invention preferably possess adequate affinity to potently inhibit B7-H1 activity, or inhibit B7-H1 binding to one or more of its cognate ligands, and preferably have an adequate duration of action to allow for infrequent dosing in humans. A prolonged duration of action will allow for less frequent and more convenient dosing schedules by alternate parenteral routes such as subcutaneous or intramuscular injection.
  • Sterile formulations can be created, for example, by filtration through sterile filtration membranes, prior to or following lyophilisation and reconstitution of the antibody.
  • the antibody ordinarily will be stored in lyophilised form or in solution.
  • Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having an adapter that allows retrieval of the formulation, such as a stopper pierceable by a hypodermic injection needle.
  • the route of antibody administration is in accord with known methods, e.g., injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intrathecal, inhalation or intralesional routes, direct injection to a tumour site, or by sustained release systems as noted below.
  • the antibody is preferably administered continuously by infusion or by bolus injection.
  • an effective amount of antibody to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred that the therapist titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Typically, the clinician will administer antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or by the assays described herein.
  • Antibodies as described herein, can be prepared in a mixture with a pharmaceutically acceptable carrier.
  • This therapeutic composition can be administered intravenously or through the nose or lung, preferably as a liquid or powder aerosol (lyophilised).
  • the composition can also be administered parenterally or subcutaneously as desired.
  • the therapeutic composition should be sterile, pyrogen-free and in a parenterally acceptable solution having due regard for pH, isotonicity, and stability. These conditions are known to those skilled in the art.
  • dosage formulations of the compounds described herein are prepared for storage or administration by mixing the compound having the desired degree of purity with pharmaceutically acceptable carriers, excipients, or stabilisers.
  • Such materials are non-toxic to the recipients at the dosages and concentrations employed, and include buffers such as TRIS HC1, phosphate, citrate, acetate and other organic acid salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium and/or nonionic surfactants such as TWEEN, PLURONICS or poly ethylenegly col.
  • buffers such as TRIS HC1, phosphate, citrate, acetate
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (20 th ed, Lippincott Williams & Wilkens Publishers (2003)). For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the polypeptide, which matrices are in the form of shaped articles, films or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) as described by Langer et al, J. Biomed Mater. Res., (1981) 15: 167-277 and Langer, Chem. Tech., (1982) 12:98-105, or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • Sustained-released compositions also include preparations of crystals of the antibody suspended in suitable formulations capable of maintaining crystals in suspension. These preparations when injected subcutaneous ly or intraperitonealy can produce a sustained release effect.
  • Other compositions also include liposomally entrapped antibodies. Liposomes containing such antibodies are prepared by methods known per se: U.S. Pat. No. DE 3,218,121; Epstein et al, Proc. Natl. Acad. Sci. USA, (1985) 82:3688-3692; Hwang et al, Proc. Natl. Acad. Sci.
  • the dosage of the antibody formulation for a given patient will be determined by the attending physician taking into consideration various factors known to modify the action of drugs including severity and type of disease, body weight, sex, diet, time and route of administration, other medications and other relevant clinical factors.
  • Therapeutically effective dosages can be determined by either in vitro or in vivo methods.
  • An effective amount of the antibodies, described herein, to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • a typical daily dosage might range from about 0.000 lmg/kg, O.OOlmg/kg, O.Olmg/kg, O.lmg/kg, lmg/kg, lOmg/kg to up to lOOmg/kg, lOOOmg/kg, lOOOOmg/kg or more, of the patient's body weight depending on the factors mentioned above.
  • the dosage may be between 0.0001 mg/kg and 20 mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5 mg/kg, 0.0001 and 2 mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and 0.75 mg/kg, 0.0001 mg/kg and 0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg, 0.0001 to 0.15 mg/kg, 0.0001 to 0.10 mg/kg, 0.001 to 0.5 mg/kg, 0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kg of the patient's body weight depending on the factors mentioned above.
  • the clinician will administer the therapeutic antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or as described herein.
  • Doses of antibodies of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • compositions and methods herein will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
  • suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
  • formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.
  • Such modalities include, without limitation, advanced antibody therapeutics, such as bispecific antibodies, immunotoxins, radiolabeled therapeutics, and single antibody V domains, antibodylike binding agent based on other than V region scaffolds, single domain antibodies, generation of peptide therapeutics, B7-H1 binding domains in novel scaffolds, gene therapies, particularly intrabodies, antisense therapeutics, and small molecules.
  • advanced antibody therapeutics such as bispecific antibodies, immunotoxins, radiolabeled therapeutics, and single antibody V domains, antibodylike binding agent based on other than V region scaffolds, single domain antibodies, generation of peptide therapeutics, B7-H1 binding domains in novel scaffolds, gene therapies, particularly intrabodies, antisense therapeutics, and small molecules.
  • An antigen binding site may be provided by means of arrangement of CDRs on non- antibody protein scaffolds, such as fibronectin or cytochrome B etc. (Haan & Maggos (2004) BioCentury, 12(5): A1-A6; Koide et al. (1998) Journal of Molecular Biology, 284: 1141-1151; Nygren et al. (1997) Current Opinion in Structural Biology, 7: 463-469) or by randomising or mutating amino acid residues of a loop within a protein scaffold to confer binding specificity for a desired target. Scaffolds for engineering novel binding sites in proteins have been reviewed in detail by Nygren et al. (Nygren et al.
  • Protein scaffolds for antibody mimics are disclosed in WO/0034784, which is herein incorporated by reference in its entirety, in which the inventors describe proteins (antibody mimics) that include a fibronectin type III domain having at least one randomised loop.
  • a suitable scaffold into which to graft one or more CDRs, e.g. a set of HCDRs, may be provided by any domain member of the immunoglobulin gene superfamily.
  • the scaffold may be a human or non-human protein.
  • An advantage of a non-antibody protein scaffold is that it may provide an antigen-binding site in a scaffold molecule that is smaller and/or easier to manufacture than at least some antibody molecules.
  • Small size of a binding member may confer useful physiological properties, such as an ability to enter cells, penetrate deep into tissues or reach targets within other structures, or to bind within protein cavities of the target antigen.
  • Use of antigen binding sites in non-antibody protein scaffolds is reviewed in Wess, 2004 (Wess, L. In: BioCentury, The Bernstein Report on BioBusiness, 12(42), A1-A7, 2004).
  • Typical are proteins having a stable backbone and one or more variable loops, in which the amino acid sequence of the loop or loops is specifically or randomly mutated to create an antigen-binding site that binds the target antigen.
  • Such proteins include the IgG-binding domains of protein A from S.
  • a targeted binding agent may comprise other amino acids, e.g.
  • Targeted binding agents of the invention may carry a detectable label, or may be conjugated to a toxin or a targeting moiety or enzyme (e.g. via a peptidyl bond or linker).
  • a targeted binding agent may comprise a catalytic site (e.g. in an enzyme domain) as well as an antigen binding site, wherein the antigen binding site binds to the antigen and thus targets the catalytic site to the antigen.
  • the catalytic site may inhibit biological function of the antigen, e.g. by cleavage.
  • bispecific antibodies can be generated that comprise (i) two antibodies one with a specificity to B7-H1 and another to a second molecule that are conjugated together, (ii) a single antibody that has one chain specific to B7-H1 and a second chain specific to a second molecule, or (iii) a single chain antibody that has specificity to B7-H1 and the other molecule.
  • Such bispecific antibodies can be generated using techniques that are well known; for example, in connection with (i) and (ii) see e.g., Fanger et al. Immunol Methods 4:72-81 (1994) and Wright and Harris, supra, and in connection with (iii) see e.g., Traunecker et al. Int. J.
  • the second specificity can be made as desired.
  • the second specificity can be made to the heavy chain activation receptors, including, without limitation, CD 16 or CD64 ⁇ see e.g., Deo et al. Immunol. Today 18:127 (1997)) or CD89 ⁇ see e.g., Valerius et al. Blood 90:4485-4492 (1997)).
  • Antibodies can also be modified to act as immunotoxins utilising techniques that are well known in the art. See e.g., Vitetta Immunol Today 14:252 (1993). See also U.S. Patent No. 5,194,594. In connection with the preparation of radiolabeled antibodies, such modified antibodies can also be readily prepared utilising techniques that are well known in the art. See e.g., Junghans et al. in Cancer Chemotherapy and Biotherapy 655-686 (2d edition, Chafner and Longo, eds., Lippincott Raven (1996)). See also U.S. Patent Nos. 4,681,581, 4,735,210, 5,101,827, 5,102,990 (RE 35,500), 5,648,471, and 5,697,902. Each immunotoxin or radiolabeled molecule would be likely to kill cells expressing the desired multimeric enzyme subunit oligomerisation domain.
  • an antibody When an antibody is linked to an agent (e.g., radioisotope, pharmaceutical composition, or a toxin) it is contemplated that the agent possesses a pharmaceutical property selected from the group of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents and combinations thereof.
  • agent e.g., radioisotope, pharmaceutical composition, or a toxin
  • the agent possesses a pharmaceutical property selected from the group of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents and combinations thereof.
  • the agent can be selected from the group of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antimetabolites, antibiotics, enzymes, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, antagonists, endostatin, taxols, camptothecins, oxaliplatin, doxorubicins and their analogs, and a combination thereof.
  • toxins further include gelonin, Pseudomonas exotoxin (PE), PE40, PE38, diphtheria toxin, ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, Pseudomonas endotoxin, members of the enediyne family of molecules, such as calicheamicin and esperamicin, as well as derivatives, combinations and modifications thereof.
  • Chemical toxins can also be taken from the group consisting of duocarmycin (see, e.g., U.S. Patent No.
  • chemotherapeutic agents also include Adriamycin, Doxorubicin, 5-Fluorouracil, Cytosine arabinoside (Ara-C), Cyclophosphamide, Thiotepa, Taxotere (docetaxel), Busulfan, Cytoxin, Taxol, Methotrexate, Cisplatin, Melphalan, Vinblastine, Bleomycin, Etoposide, Ifosfamide, Mitomycin C, Mitoxantrone, Vincreistine, Vinorelbine, Carboplatin, Teniposide, Daunomycin, Carminomycin, Aminopterin, Dactinomycin, Mitomycins, Esperamicins (see, U.S.
  • Patent No. 4,675,187 Melphalan, and other related nitrogen mustards.
  • Suitable toxins and chemotherapeutic agents are described in Remington's Pharmaceutical Sciences, 19th Ed. (Mack Publishing Co. 1995), and in Goodman And Gilman's The Pharmacological Basis of Therapeutics, 7th Ed. (MacMillan Publishing Co. 1985).
  • Other suitable toxins and/or chemotherapeutic agents are known to those of skill in the art.
  • radioisotopes examples include gamma-emitters, positron-emitters, and x-ray emitters that can be used for localisation and/or therapy, and beta-emitters and alpha-emitters that can be used for therapy.
  • the radioisotopes described previously as useful for diagnostics, prognostics and staging are also useful for therapeutics.
  • Non-limiting examples of anti-cancer or anti-leukemia agents include anthracyclines such as doxorubicin (adriamycin), daunorubicin (daunomycin), idarubicin, detorubicin, carminomycin, epirubicin, esorubicin, and morpholino and substituted derivatives, combinations and modifications thereof.
  • anthracyclines such as doxorubicin (adriamycin), daunorubicin (daunomycin), idarubicin, detorubicin, carminomycin, epirubicin, esorubicin, and morpholino and substituted derivatives, combinations and modifications thereof.
  • Exemplary pharmaceutical agents include cis-platinum, taxol, calicheamicin, vincristine, cytarabine (Ara-C), cyclophosphamide, prednisone, daunorubicin, idarubicin, fludarabine, chlorambucil, interferon alpha, hydroxyurea, temozolomide, thalidomide, and bleomycin, and derivatives, combinations and modifications thereof.
  • the anti- cancer or anti-leukemia is doxorubicin, morpholinodoxorubicin, or morpholinodaunorubicin.
  • the antibodies of the invention also encompass antibodies that have half-lives (e.g., serum half-lives) in a mammal, preferably a human, of greater than that of an unmodified antibody.
  • said antibody half life is greater than about 15 days, greater than about 20 days, greater than about 25 days, greater than about 30 days, greater than about 35 days, greater than about 40 days, greater than about 45 days, greater than about 2 months, greater than about 3 months, greater than about 4 months, or greater than about 5 months.
  • Antibodies or fragments thereof having increased in vivo half-lives can be generated by techniques known to those of skill in the art. For example, antibodies or fragments thereof with increased in vivo half-lives can be generated by modifying (e.g., substituting, deleting or adding) amino acid residues identified as involved in the interaction between the Fc domain and the FcRn receptor (see, e.g., International Publication Nos.
  • Antibodies or fragments thereof with increased in vivo half-lives can be generated by attaching to said antibodies or antibody fragments polymer molecules such as high molecular weight polyethyleneglycol (PEG).
  • PEG polymer molecules
  • PEG can be attached to said antibodies or antibody fragments with or without a multifunctional linker either through site-specific conjugation of the PEG to the N- or C-terminus of said antibodies or antibody fragments or via epsilon-amino groups present on lysine residues. Linear or branched polymer derivatisation that results in minimal loss of biological activity will be used.
  • the degree of conjugation will be closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of PEG molecules to the antibodies. Unreacted PEG can be separated from antibody- PEG conjugates by, e.g., size exclusion or ion-exchange chromatography.
  • affinity values can be important, other factors can be as important or more so, depending upon the particular function of the antibody.
  • an immunotoxin toxin associated with an antibody
  • the act of binding of the antibody to the target can be useful; however, in some embodiments, it is the internalisation of the toxin into the cell that is the desired end result.
  • antibodies with a high percent internalisation can be desirable in these situations.
  • antibodies with a high efficiency in internalisation are contemplated.
  • a high efficiency of internalisation can be measured as a percent internalised antibody, and can be from a low value to 100%.
  • 0.1-5, 5-10, 10-20, 20-30, 30-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-99, and 99-100% can be a high efficiency.
  • the desirable efficiency can be different in different embodiments, depending upon, for example, the associated agent, the amount of antibody that can be administered to an area, the side effects of the antibody-agent complex, the type (e.g., cancer type) and severity of the problem to be treated.
  • the antibodies disclosed herein provide an assay kit for the detection of B7-H1 expression in mammalian tissues or cells in order to screen for a disease or disorder associated with changes in expression of B7-H1.
  • the kit comprises an antibody that binds B7-H1 and means for indicating the reaction of the antibody with the antigen, if present.
  • an article of manufacture comprising a container, comprising a composition containing an antibody that specifically binds B7-H1 , and a package insert or label indicating that the composition can be used to treat disease mediated by B7-H1 expression.
  • a mammal and, more preferably, a human receives the antibody that specifically binds B7-H1.
  • the anti-tumour treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery, bone marrow and peripheral stem cell transplantations or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vin
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetra
  • metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or inhibitors of cathepsin activity, inhibitors of serine proteases for example matriptase, hepsin, urokinase and inhibitors of integrin ⁇ 6 function.
  • cytotoxic agents such as fludarabine, 2-chlorodeoxyadenosine, chlorambucil or doxorubicin and combination thereoff such as Fludarabine + cyclophosphamide, CVP: cyclophosphamide + vincristine + prednisone, ACVBP: doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone, CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone, CNOP: cyclophosphamide + mitoxantrone + vincristine + prednisone, m-BACOD: methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone + leucovorin., MACOP-B: methotrexate + doxorubicin + cyclophosphamide, vin
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3 -chloro-4-fluorophenyl)-7-(3 -morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM)] and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2- fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications W097/22596, WO
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense or G3139 (Genasense), an anti bcl2 antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) immunotherapy approaches including for example treatment with Alemtuzumab (campath-lHTM), a monoclonal antibody directed at CD52, or treatment with antibodies directed at CD22, ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy such as treatment with monoclonal antibodies inhibiting CTLA-4 function, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies, adoptive T-cell transfer using T-cells that have been non-specifically activated or targeted to a specific antigen of interest ex vivo;
  • cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor
  • approaches to decrease T cell anergy such as treatment with monoclonal antibodies inhibit
  • Vaccination approaches including for example treatment with a vaccine directed against a specific viral infection such as HIV or HBV, or treatment with a vaccine directed against a specific tumour antigen;
  • inhibitors of protein degradation such as proteasome inhibitor such as Velcade (bortezomid); and
  • biotherapeutic therapeutic approaches for example those which use peptides or proteins (such as antibodies or soluble external receptor domain constructions) which either sequester receptor ligands, block ligand binding to receptor or decrease receptor signalling (e.g. due to enhanced receptor degradation or lowered expression levels).
  • peptides or proteins such as antibodies or soluble external receptor domain constructions
  • the anti-tumour treatment defined herein may involve, in addition to the compounds of the invention, treatment with other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxalip latin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range.
  • the human B7-H1 cDNA (Dong, H. et al, 1999, Nat. Med. 5: 1365 - 1369) was amplified from Image clone 7262208 (ATCC) using polymerase chain reaction (PCR) and then cloned into the Nhe 1 and EcoRl sites of pcr3.1Bid vector. This construct was lipofected into CHO cells (American Type Tissue Collection, catalog # CCL-61) and the expression on the cell surface was confirmed by fluorescent activated cell sorting (FACS) analysis.
  • FACS fluorescent activated cell sorting
  • Monoclonal antibodies against human B7-H1 were developed by sequentially immunizing XenoMouse ® mice (XenoMouse strains: XMG2 (IgG2 kappa/lambda) and XMG4 (IgG4 kappa/lambda) Amgen, Inc. Vancouver, British Columbia, Canada) with either 5-10 ug of the B7-Hl/Fc chimera protein or 1-2x10(6) CHO cells expressing recombinant human B7-H1 as described in Example 1.
  • refers to "intraperitoneal” and "SC” refers to "subcutaneous'
  • EXAMPLE 3 RECOVERY OF LYMPHOCYTES, B-CELL ISOLATIONS, FUSIONS
  • Immunised mice were sacrificed by cervical dislocation, and the draining lymph nodes harvested and pooled from each cohort.
  • the lymphoid cells were dissociated by grinding in DMEM to release the cells from the tissues and the cells were suspended in DMEM. The cells were counted, and 0.9 ml DMEM per 100 million lymphocytes added to the cell pellet to resuspend the cells gently but completely.
  • Using 100 ⁇ of CD90+ magnetic beads per 100 million cells the cells were labeled by incubating the cells with the magnetic beads at 4°C for 15 minutes.
  • the magnetically labeled cell suspension containing up to 10 8 positive cells (or up to 2xl0 9 total cells) was loaded onto a LS+ column and the column washed with DMEM. The total effluent was collected as the CD90-negative fraction (most of these cells were expected to be B cells).
  • the fusion was performed by mixing washed enriched B cells from above and nonsecretory myeloma P3X63Ag8.653 cells purchased from ATCC, cat.# CRL 1580 (Kearney et al, J. Immunol. 123, 1979, 1548-1550) at a ratio of 1 :1.
  • the cell mixture was gently pelleted by centrifugation at 800 x g. After complete removal of the supernatant, the cells were treated with 2-4 mL of Pronase solution (CalBiochem, cat. # 53702; 0.5 mg/ml in PBS) for no more than 2 minutes.
  • Electro-cell fusion was performed using a fusion generator (model ECM2001, Genetronic, Inc., San Diego, CA).
  • the fusion chamber size used was 2.0 ml, using the following instrument settings:
  • the cell suspensions were carefully removed from the fusion chamber under sterile conditions and transferred into a sterile tube containing the same volume of Hybridoma Culture Medium (DMEM, JRH Biosciences), 15 % FBS (Hyclone), supplemented with L- glutamine, pen/strep, OPI (oxaloacetate, pyruvate, bovine insulin) (all from Sigma) and IL-6 (Boehringer Mannheim).
  • DMEM Hybridoma Culture Medium
  • FBS Hyclone
  • OPI oxaloacetate, pyruvate, bovine insulin
  • IL-6 Boehringer Mannheim
  • Hybridoma Selection Medium Hybridoma Culture Medium supplemented with 0.5x HA (Sigma, cat. # A9666)
  • Hybridoma Selection Medium 0.5x HA (Sigma, cat. # A9666)
  • the cells were mixed gently and pipetted into 96-well plates and allowed to grow. On day 7 or 10, one-half the medium was removed, and the cells re-fed with Hybridoma Selection Medium.
  • Hybridomas were grown as routine in the selective medium. Exhaustive supernatants collected from the hybridomas were tested in various assays as described in Examples 4-5. Just to note, antibodies that begin with a 3 digit, e.g., 3.15G8, are IgG4 and antibodies that begin with a 2, e.g., 2.9D10, are IgG2.
  • EXAMPLE 4 BINDING TO CELL BOUND HUMAN AND CYNOMOLGUS MONKEY
  • Supernatants collected from hybridoma cells were tested to assess the ability of the secreted antibodies to bind to 293T cells transiently expressing either full length human or cynomolgus monkey B7-H1.
  • a mock-transfected 293T cell line was used as a negative control.
  • Cells diluted in PBS containing 2% FBS were seeded at a density of 2500-3000 expressing and 15000-17500 mock transfected cells in 40 ⁇ /well in 384 well plates (Corning Costar, catalog # 3712). Immediately after plating, 10 ⁇ /well of hybridoma supernatants were added and plates incubated for 1.5 hr at room temperature.
  • Biotinylated human PD-l/Fc protein (R&D Systems, catalog #1086-PD) was added to a final concentration of 1.25 ug/ml and plates were incubated at 4C for 1 hour on a shaker. Cells were washed and fixed in 100 ul of PBS containing 3.7% formaldehyde and 3% bovine serum albumin for 20 min at room temperature. Cells were washed and incubated in 100 ul of PBS containing 0.6% H202 and 3% bovine serum albumin for 10 min at room temperature. Cells were washed and incubated in 50 ⁇ of horseradish peroxidase-conjugated streptavidin diluted at 1 :4000 for 30 min at 4oC.
  • the ability of the purified antibodies to bind to human B7-H1, B7-DC, mouse B7H1 and cynomolgus monkey B7-H1 was determined by FACS analysis. Briefly, 293T cells were either mock-transfected or transiently transfected with either human B7-H1 or human B7-DC using Lipofectamine 2000 (Invitrogen, catalog #11668). Mouse J558 cells expressing mouse B7-H1 were obtained from ATCC (catalog #TIB-6). Cells were resuspended in PBS containing 2%> FBS (FACS buffer) and seeded at 50000 cells/well into V-bottomed plates.
  • FACS buffer FACS buffer
  • Anti-B7-Hl and isotype control antibodies diluted in FACS buffer were added at a final concentration of 5 ⁇ g/ml and plates were incubated for 1 h at 4 °C. After washing with FACS buffer, goat anti-human Fc Cy5 (5 ⁇ g/ml, Jackson Immunoresearch, catalog # 109-175-098) and 7-AAD (5 ⁇ g/ml) were added and plates were incubated for 15 min at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Table 5 shows ability of purified antibodies (5 ⁇ g/ml) to bind to 293T cells transfected with human B7-H1.
  • EXAMPLE 7 BINDING OF PURIFIED HUMAN ANTI-B7-H1 ANTIBODIES TO STIMULATED HUMAN AND CYNOMOLGUS MONKEY T CELLS
  • 96-well high binding plates were incubated with 100 ul/well of anti-CD3 antibody diluted at 1 ug/ml in PBS (OKT3 clone, eBioscience, catalog # 160037) at 4C overnight.
  • Human T cells were isolated from frozen leukopack using T cell enrichment kit (StemCell Technologies, catalog #19051).
  • Anti-CD3 mAb coated plates were washed with PBS and purified T cells were added in 200 ul of ICM media at 360000 cells/well and cultured for 72 hours.
  • T cells were then harvested, washed in FACS buffer and mixed with diluted purified anti-B7-Hl antibodies or irrelevant human IgG2 or IgG4 antibodies at final concentration of lug/ml in 96-well V-bottom assay plate (50 ul/well). After 2 hours incubation at 4C, T cells were washed twice in FACS buffer and then stained with Cy5 -conjugated goat anti-human IgG Fc antibody (5 ug/ml, Jackson Immunoresearch, catalog # 109-175-098) and 7-AAD (10 ug/ml). Cells were incubated for 30 min at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Live lymphocyte population was selected for analysis based on forward and side scatter as well as negative staining for 7-AAD.
  • 96-well high binding plates were incubated with 100 ul/well of goat anti-mouse IgG Fc antibody diluted at 1 ug/ml in PBS at 4C overnight. Plates were washed with PBS and incubated with anti-CD3 antibody diluted at 1 ug/ml in ICM media (clone SP-34, BD catalog #556610) at 37C for 2 hours. Cynomolgus monkey PBMC were isolated from peripheral blood (Bioreclamation, catalog #CYNWBCPT). Anti-CD3 mAb coated plates were washed with PBS and isolated PBMC were added in 200 ul of ICM media at -200000 cells/well and cultured for 72 hours.
  • the ability of purified human anti-B7-Hl antibodies to inhibit the binding of human PD-l/Fc protein to human B7-H1 expressed on surface of ES-2 cells was evaluated. Briefly, 50000 cells/well were plated in 50 ⁇ of PBS into wells of a 384-well tissue culture plate (Corning Costar, catalog # 3712). Next, 50 ⁇ /well of a diluted monoclonal antibody was added at final concentration of 2.5, 0.5, 0.1, 0.02, 0.004, 0.008, 0.00016 nM and plates were incubated at 4C for 1 hour.
  • Biotinylated human PD-l/Fc protein (10 ug/ml, R&D Systems, catalog #1086-PD) was added and plates were incubated at 4C for 1 hour.
  • EXAMPLE 9 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES
  • CD3-coated beads/ml were further coupled with recombinant human IgGlFc (R&D Systems, cat# l lO-HG-100) at 160 ug/ml or with the recombinant human B7-Hl/Fc protein (R&D Systems, Cat# 156-B7-100) at 80 ug/ml combined with the human IgGlFc protein at 80 ug/ml (total concentration 160 ug/ml) and incubated at 37°C for 24 hours with shaking.
  • human IgGlFc R&D Systems, cat# l lO-HG-100
  • B7-Hl/Fc protein R&D Systems, Cat# 156-B7-100
  • the beads were then incubated in PBS containing 0.05% bovine serum albumin at room temperature for 1 hour, washed four times in 0.1% BSA and 2mM EDTA in PBS (pH7.4) and finally resuspended in RPMI1640 media containing 10% FBS at 5x10(7) beads/ml.
  • Peripheral blood monocytes were isolated from a leukapheresis pack using Ficoll-Paque
  • T cells were plated at 10(5) cells/80 ul/well in 96-well plate (Corning, cat#3603) and bead-antibody mix was added at 20ul/well to a total volume of 100 ul/well.
  • T cell activation in the absence of B7-H1 inhibitory effect was determined using beads coated with anti-CD3 antibody and the human IgGlFc protein.
  • Cells were cultured for 5 days and supernatants were harvested and analyzed for IFN- ⁇ release by using BD Human IFN- ⁇ ELISA Kit II (BD Cat. No.550612) per manufacturer's instructions. Cell proliferation was measured on day 5 by the addition of ⁇ /well of AlamarBlue (Invitrogen DAL 1025).
  • EXAMPLE 10 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON ACTIVATION OF CD4 T CELLS IN DENDRITIC CELL-T-CELL MIXED
  • Dendritic cells were generated from monocytic precursors as described previously (Curr Protoc Immunol. 2001 May; Chapter 7: Unit 7.32).
  • Peripheral blood monocytes were isolated from a leukapheresis pack using Ficoll-Paque Plus (GE Healthcare 17-1440-03) density gradient centrifugation, resuspended in serum-free RPMI 1640 (Gibco 22400-089), and allowed to adhere to T150 cell culture flasks (Corning 430825).
  • the nonadherent cells were removed and the cells were cultured in RPMI supplemented with 5% human serum (Invitrogen 34005100).
  • Cytokines were added at a final concentration of 2ng/ml GM-CSF (BD Biosciences 550068) and lOng/ml IL-4 (BD Biosciences 554605).
  • Fresh media with cytokines was added every 2 - 3 days.
  • cells were matured with 20ng/ml of TNF-a (BD Biosciences 554618) and allowed to incubate for 24 hours. Mature dendritic cells were harvested, phenotyped, and frozen for later use.
  • CD4+ T-cells were isolated from PBMC using a magnetic isolation kit (Dynal 113.17) per manufacturer's instructions and cultured in a primary MLR as described previously (J Immunol. 2003 Apr l;170(7):3637-44).
  • 1.5E5 allogeneic CD4+ responding T-cells were cultured in 96 well-flat bottom microtiter plates (Costar 3595) with dendritic cells at a T-cell: dendritic cell ratio of 1 :2.5.
  • Dendritic cell preparations were treated with 100 ⁇ g/ml of mitomycin C (Sigma M4287) prior to addition to coculture to prevent any proliferation from contaminating lymphocytes.
  • Antibodies were added at various concentrations in a final volume of 200 ⁇ 1 of RPMI + 10% human serum. Thymidine incorporation was measured on Day 5 by a 16-h pulse with [ 3 H] thymidine ( ⁇ ⁇ , Perkin-Elmer NET027001MC). Supernatants were harvested prior to radioactive labeling and analyzed for IFN- ⁇ release by Luminex assay (BioRad 171 -Bl 1921) per manufacturer's instructions. Enhancement of T-cell proliferation by anti-B7-Hl antibodies from repeat experiments is shown in Figure 2. Corresponding IFN- ⁇ release is shown in Figure 3.
  • the heavy chain variable domain sequences and the light chain variable domain sequence s of the antibodies were sequenced to determine their DNA sequences.
  • the complete sequence information for the anti-B7-Hl antibodies is provided in the sequence listing with nucleotide and amino acid sequences for each gamma and kappa or lambda chain combination.
  • the variable heavy sequences were analyzed to determine the VH family and the J-region sequence.
  • the sequences were then translated to determine the primary amino acid sequence and compared to the germline VH and J-region sequences to assess somatic hypermutations.
  • Tables 8 and 9 are tables comparing the antibody heavy chain regions to their cognate germline heavy chain region and the antibody light chain regions to their cognate germline light chain region.
  • the amino acid numbering is by numerical numbering.
  • Immunoglobulin genes undergo various modifications during maturation of the immune response, including recombination between V, D and J gene segments, isotype switching, and hypermutation in the variable regions. Recombination and somatic hypermutation are the foundation for generation of antibody diversity and affinity maturation, but they can also generate sequence liabilities that may make commercial production of such immunoglobulins as therapeutic agents difficult, or increase the immunogenicity risk of the antibody.
  • mutations in CDR regions are likely to contribute to improved affinity and function, while mutations in framework regions may increase the risk of immunogenicity. This risk can be reduced by reverting framework mutations to germline, while ensuring that activity of the antibody is not adversely impacted.
  • Some structural liabilities may be generated by the diversification processes, or they may exist within germline sequences contributing to the heavy and light chain variable domains. Regardless of the source, it may be desirable to remove potential structural liabilities that may result in instability, aggregation, heterogeneity of product, or increased immunogenicity. Examples of undesirable liabilities include unpaired cysteines (which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation), N-linked glycosylation sites (resulting in heterogeneity of structure and activity), as well as deamidation (e.g. NG, NS), isomerization (DG), oxidation (exposed methionine), and hydrolysis (DP) sites.
  • unpaired cysteines which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation
  • N-linked glycosylation sites resulting in heterogeneity of structure and activity
  • deamidation e.g. NG, NS
  • DG isomerization
  • the antibody sequence can be mutated back to the germline sequence.
  • Such corrective mutations can occur at one, two, three or more positions, or a combination of any of the mutated positions, using standard molecular biological techniques.
  • Tables 10-14 below illustrate the positions of such variations back to germline for mAb 2.9D10, 2.7A4 and 2.14H9. Each row represents a unique combination of germline and non-germline residues at the position indicated by bold type. The position of the amino acid is representated by numerical numbering.
  • the invention includes replacing any structural liabilities in the sequence that might affect the heterogeneity of the antibodies of the invention.
  • Such liabilities include glycosylation sites, un-paired cysteines, surface exposed methinones, etc.
  • changes are made to remove one or more of such structural liabilities.
  • N-linked glycosylation sites it may be desirable to remove one or more consensus N-linked glycosylation sites from the antibody germline or antibody sequence.
  • an N-linked glycosylation consensus site sequence has the sequence of Asn-any AA- Ser or Thr where the middle amino acid cannot be a proline (Pro).
  • unpaired cysteines can be replaced alone or in conjunction with other structural changes. An unpaired cysteine can be mutated to an appropriate amino acid that has comparable side chain properties such as a serine.
  • a sequence that is optimized is a sequence which has been mutated at one or more positions back to its germline sequence or can be modified to remove one or more other liabilities such as structural liabilities.
  • An optimized sequence can also include a sequence that has been mutated at one or more positions back to its germline sequence and which has also been further modified to remove one or more structural liabilities.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2.
  • SEQ ID NO.: 2 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 10.
  • SEQ ID NO: 2 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 10.
  • SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10.
  • the non germline sequence is mutated back to germline at position 80 where F is changed to a Y and at position 87 where K is changed to an R.
  • a specific example of such a sequence is 2.7A4VHOPT as shown in Table 15.
  • Table 11 Exemplary Mutations of 2.7A4 Light Chain (SEQ ID NO: 7) to Germline at the Indicated Residue Number
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7.
  • SEQ ID NO.: 7 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 11.
  • SEQ ID NO: 7 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 11.
  • SEQ ID NO.: 7 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11.
  • 2.7A4 variable light domain which has been mutated to particular germline sequences include 2.7A4 VLOPT (optimized where the non- germline sequence has been mutated from an A to a T at position 17 and a R to a K at position 104) as shown in Table 15.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12.
  • SEQ ID NO.: 12 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 12.
  • SEQ ID NO: 12 comprises any one, any two, or all two of the germline residues as indicated in Table 12.
  • SEQ ID NO.: 12 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 12.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17.
  • SEQ ID NO.: 17 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 13.
  • SEQ ID NO: 17 comprises any one, any two, any three, any four, or all four of the germline residues as indicated in Table 7.
  • SEQ ID NO.: 17 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 13.
  • SEQ ID NO: 17 can be altered or further altered by making nongermlining changes to SEQ ID NO: 17. In one example, SEQ ID NO: 17 can be altered such that from a F to a Y at position 37 and from a F to a Y at position 50.
  • the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27.
  • SEQ ID NO.: 27 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 14.
  • SEQ ID NO: 27 comprises any one, any two, any three, or all three of the germline residues as indicated in Table 14.
  • SEQ ID NO.: 27 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 14.
  • the heavy chain of 2.14H9 can be changed at amino acid 31 of SEQ ID NO:22 from a R to a S.
  • Germlining of these amino acid residues was carried out using standard site directed mutagenesis techniques with the appropriate mutagenic primers.
  • the germlined sequences have the prefix "OPT" after the antibody name, for example, 2.7A4VHOPT, 2.7VLOPT and 2.14H9VLOPT.
  • Germlined IgG were then re-evaluated in the human B7-Hl/hPDl ligand inhibition assay to confirm there had not been a reduction in antibody in vitro activity.
  • Example of gene synthesis and reformatting as IgGl and IgGl-TM Clones were converted from scFv to IgG format by sub-cloning the VH and VL domains into vectors expressing whole antibody heavy and light chains respectively.
  • the VH domains were cloned into the vector pEU15.1 to express IgGl or the vector pEU15.1-TM to express IgGl-TM antibodies.
  • Both vectors contain the human heavy chain constant domains and regulatory elements to express whole IgG heavy chain in mammalian cells.
  • the vector pEU15.1- TM is a modified pEU15.1 human IgGl vector.
  • VL domains were cloned into pEU4.4 and pEU3.4 vectors for the expression of the human lambda and kappa light chain constant domains respectively, with regulatory elements to express whole IgG light chain in mammalian cells.
  • Vectors for the expression of heavy chains and light chains were originally described in Vaughan et al. (Nature Biotechnology 14(3):309- 314, 1996). These vectors have been engineered simply by introducing an OriP element.
  • IgGs the heavy and light chain IgG expression vectors were transfected into EBNA-HEK293 mammalian cells (Invitrogen R620-07). IgGs were expressed and secreted into the medium. Harvests were pooled and spun down prior to purification. The IgG was purified using Protein A chromatography using an AKTA Express purification system (GE Healthcare) previously sanitised to avoid any endotoxin contamination of the sample. Culture supernatants are loaded onto lmL HiTrapTM MabSelectSureTM columns (GE Healthcare, 11-0034-93) and washed with 50 mM Tris-HCl pH 8.0, 250 mM NaCl.
  • AKTA Express purification system GE Healthcare
  • Bound IgG was eluted from the column using 0.1 M Sodium Citrate (pH 3.0) and neutralised by the addition of 1M Tris-HCl (pH 9.0). The eluted material was buffer exchanged into PBS using Nap 10 columns (Amersham, 17-0854- 02) and filtered before determining protein concentration and endotoxin levels. IgG concentration was determined spectrophotometrically using an extinction coefficient based on the amino acid sequence of the IgG (Vaughan et al. supra).
  • Endotoxin level was determined using the Endosafe PTS Portable Test System (Charles River Laboratories) fitted with 1-0.1 EU/mL and 10- O.lEU/mL LAL cartridges (Charles River Laboratories, PT520). The purified IgG were analysed for degradation by SDS-PAGE.
  • Anti-B7-Hl antibodies in the IgGl-TM format were evaluated and compared to the same antibodies but in the IgGl format in the human B7-Hl/hPDl ligand inhibition assay to confirm there had not been a reduction in antibody in vitro activity due to IgG isotype switching ( Figure 4) ⁇
  • EXAMPLE 12 HUMAN B7H1/FC BINDING HUMAN PD1/FC - HTRF® ASSAY
  • the assay described is a homogenous TR-FRET assay using HTRF ® assay technology requiring no wash steps.
  • To a Costar 3676 microtitre plate 5 ⁇ 1 ⁇ 11 of biotinylated PDl/Fc at InM diluted into PBS was added. This was followed with the addition of 5 ⁇ 1 ⁇ 11 streptavidin XL ent (CisBio) at 4nM diluted into assay buffer (PBS + 0.1% BSA + 0.8M KF). 5 ⁇ 1 ⁇ 11 of a titration of sample material diluted in PBS was added to relevant wells. For the definition of total binding, 5 ⁇ 1 of PBS or relevant sample buffer was added per well.
  • Example of IC50 determinations in the human PDl/human B7-H1 ligand inhibition assay for anti-B7-Hl antibodies are provided in Table 19. All anti-human B7-H1 antibodies are in the IgGl-TM format.
  • EXAMPLE 13 HUMAN B7H1/FC BINDING HUMAN B7-1/FC - HTRF ® ASSAY
  • the assay described was a homogenous TR-FRET assay using HTRF ® assay technology requiring no wash steps.
  • To a Costar 3676 microtitre plate 5 ⁇ 1 ⁇ 11 of biotinylated B7-1/Fc at 8nM diluted into PBS was added. This was followed with the addition of 5 ⁇ 1 ⁇ 11 streptavidin XL ent (CisBio) at 20nM diluted into assay buffer (PBS + 0.1% BSA + 0.8M KF). 5 ⁇ 1 ⁇ 11 of a titration of sample material diluted in PBS was added to relevant wells. For the definition of total binding, 5 ⁇ 1 of PBS or relevant sample buffer per well was added.
  • EXAMPLE 14 CROSS REACTIVITY OF ANTI-B7-H1 ANTIBODIES WITH OTHER
  • ELISAs were performed to determine the cross-reactivity of the anti-B7-Hl IgGl-TM antibodies for other immune co-modulatory molecules.
  • the ELISAs consisted of coating MaxiSorp plates (NUNC) at 4° C overnight with 250ng per well of the extracellular domain (ECD) of human B7-H1 (R&D Systems, 156-B7), human PD-L2 (R&D Systems, 1224-PL), human B7-H2 (R&D Systems, 165-B7), human B7-H3 (R&D Systems, 1027-B3), human CD28 (R&D Systems, 342-CD), human CTLA-4 (R&D Systems, 325-CT) and human PD1 (R&D Systems, 1086-PD) followed by blocking the plates with PBS containing 3% dried milk powder at room temperature for lh.
  • NUNC MaxiSorp plates
  • Murine cross reactivity was also investigated by coating the ECD of murine B7-H1 (R&D Systems, 1019-B7).
  • Biotinylated anti-B7-Hl IgGl-TM diluted at ⁇ in PBS containing 3% dried milk powder, were incubated at room temperature for 2h to allow binding. Bound biotinylated IgGs were detected with europium Nl -labelled streptavidin (Perkin Elmer, 1244-360) at 0.2ug/mL.
  • Control experiment demonstrating antigen coating to the NUNC plate was performed using the commercial antibodies mouse IgG2a anti-human B7-H1 (R&D Systems, MAB156), mouse IgG2b anti-human PD-L2 (R&D Systems, MAB1224), mouse IgG2b anti-human B7-H2 (R&D Systems, MAB165), mouse IgGl anti-human B7-H3 (R&D Systems, MAB1027), mouse IgGl anti-human CD28 (R&D Systems, MAB342), mouse IgG2a anti-human CTLA-4 (Abeam, ab33320), mouse IgG2b anti-human PD1 (R&D Systems, MAB1086) and rat IgG2a anti-mouse B7-H1 (R&D Systems, MAB1019).
  • mouse IgG2a anti-human B7-H1 R&D Systems, MAB156
  • mouse IgG2b anti-human PD-L2 R&D Systems, MA
  • the cross-reactivity of the 3 anti-B7-Hl IgGl-TM antibodies 2.7A40PT, 2.9D10 and 2.14H90PT to the panel of eight immune co-modulatory antigens were determined in triplicate. At lOOnM of antibody concentration, all three anti-B7-Hl antibodies show no cross reactivity for any of the seven human immune co-modulatory molecules we tested ( Figure 5).
  • the IgGl-TM anti-B7-Hl antibody 2.7A40PT displays a measurable cross reactivity for murine B7-H1 with a signal level of 5.3% on average compared to 100% binding to the human B7-H1.
  • the other two anti-B7-Hl antibodies tested, 2.9D10 and 2.14H90PT do not show any cross reactivity for murine B7-H1 ( Figure 5).
  • EXAMPLE 15 AFFINITY OF ANTI-B7-H1 ANTIBODIES FOR HUMAN AND
  • the binding affinity and kinetic parameters of anti-B7-Hl antibodies in the IgGl-TM format to monomeric human and cynomologus B7-H1 were determined by surface plasmon resonance using a BIAcore T100 instrument (BIAcore, Uppsala, Sweden). In brief, experiments were performed at 25°C using HBS-EP buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% v/v surfactant P20) as running buffer.
  • IgGs were affinity captured on the surface of a CM5 sensor chip (BIAcore) via protein G, which was amine coupled onto the CM5 surface to achieve the density of -500 Response Units (RU), according to the manufacturer's instructions (BIAapplications Handbook, BIAcore).
  • Recombinant monomeric human or cynomologus B7-H1 FlagHisio extracellular domains (ECDs) were used as analytes. Dilutions of B7-H1 ECD (200- 3.12 nM) in the running buffer were injected at a constant flow rate of 100 ⁇ /min for 60 seconds.
  • Hl is InM and 175pM respectively (Table 21).
  • Affinity of anti-B7-Hl antibodies 2.7A40PT and 2.14H90PT for monomeric cynomologus B7-H1 is 835pM and 367pM respectively (Table 22). Those two antibodies are strongly cross reactive for cynomologus B7-H1 as affinities are very close to the ones for human B7-H1.
  • Table 22 Affinity and kinetic parameters analysis of anti-B7-Hl antibodies for binding to cynomologus B7-H1 Reference Antibody #1 4.64 1.36xl0 6 0.0063
  • EXAMPLE 16 EPITOPE MAPPING OF ANTI-B7-H1 ANTIBODIES
  • Anti-B7-Hl antibodies are competing for the binding of human B7-H1 to human PD1 (Example 5, 8 and 12) so they should interact with some of those 14 residues if we assume that there are negligible differences between the B7H1 binding interface to human and mouse PD1 (62% amino acid identity between the two species extracellular domain sequence). Single amino acid B7-H1 mutants will be generated for all the 14 positions described in Table 23. Mutants will be tested for binding to anti-B7-Hl antibodies by phage ELISA and the ability to compete the binding of anti-B7-Hl antibodies to human B7-H1 in HTRF ® competition assays. All anti-B7-Hl antibodies described are in the IgGl-TM format. Cloning of the human B7-H1 extracellular domain gene in fusion with bacteriophage gene III for phage display expression
  • B7H1 REV 5 '-AATAATGCGGCCGCCCTTTCGTTTGGGGGATGC-3 '
  • PCR product has then been directionally cloned in the pCANTAB6 vector (McCafferty J. et al, 1994, Appl. Biochem. BiotechnoL, Vol. 47, pl57- 173) using Sfi I and Not I restriction sites.
  • E. coli strain TGI were transformed with the ligation and individual colonies were screened by sequencing to identify a B7-H1 transformant named B7-Hl_pCANTA6.
  • B7-H1 mutants have been generated by saturation mutagenesis at all the 14 residues of the PD1 interface using fully randomised NNS primers (Table 24) and the plasmid B7- Hl_pCANTA6 as DNA template. Mutagenesis was performed with the Stratagene's QuickChange Multi Site-Directed Mutagenesis Kit (Catalog #200513) according to the manufacturer's instructions. Mutagenic reactions were used to transform E. coli strain TGI and individual colonies were screened by sequencing to identify B7-H1 variants. A total of 252 variants were identified among the 280 possible (20 amino acids time 14 positions) and cherry picked in 3 96-wells culture plates.
  • Binding of the B7-H1 mutants to anti-B7-Hl antibodies 2.14H90PT, 2.7A40PT or Reference Ab#l have been assessed by phage ELISA after assuring that the B7-H1 extracellular domain in fusion with gene III protein could be displayed at the phage surface.
  • Cherry picked TGI cultures were grown and superinfected with M13K07 helper phage to produce phage particles displaying B7-H1 mutants at their surface.
  • Phage supernatants were blocked in PBS+3% skimmed milk and incubated in NUNC MaxiSorb plates previously coated overnight with lug/mL 2.14H90PT, 2.7A40PT or Reference antibody#l in PBS and blocked with PBS+3% skimmed milk.
  • Bound phages were detected using streptavidin coupled with europium (Perkin Elmer) after incubation with a biotinylated anti-M13 secondary antibody (Progen).
  • Extracellular domain of human B7-H1 wild-type and mutants were expressed in bacteria and purified by affinity chromatography as previously described (Bannister D. et ah, 2006, Biotechnology and bioengineering, 94, 931-937).
  • the HTRF® competition assays measured the binding of anti-B7-Hl antibody to HIS FLAG tagged B7-H1. Titration of non tagged B7-H1 samples, prepared as described above, will compete with HIS FLAG tagged B7-H1 for binding to anti-B7-Hl antibody, leading to a reduction in assay signal.
  • the antibodies 2.14H90PT, 2.7A40PT and Reference antibody#l were used to establish competition assays for characterising the relative binding of purified wild- type or mutants B7-H1. This will confirm which B7-H1 residues are required for antibody binding. 10 ⁇ of B7-H1 sample was added to a 384 well low volume assay plate (Corning 3673).
  • B7-H1 sample 2.14H90PT IgGLTM 2.7A40PT IgGLTM Reference Ab#1 wild-type B7H1 0.76 2.79 1.89
  • B7H1 R125S No inhibition 2.7 9.7 Argl 13 and Argl 25 are strongly involved in the binding to 2.14H90PT.
  • Replacement by an Ala or other amino acids (Tyr or Leu at position 113 and Gin or Ser at position 125) lead to a total lost of binding to that antibody.
  • Binding profile of those B7-H1 mutants to 2.7A40PT or Reference antibody#l is similar to the wild-type B7-H1. This shows that the lost of binding is not due to a general structural modification of B7-H1 as for instance an unfolded protein but to a direct involvement of those residues with 2.14H90PT binding.
  • Phel9, Thr20 and Aspl22 are strongly involved in the binding to 2.7A40PT. All B7-H1 mutants at those positions have no binding to that antibody but do bind 2.14H90PT or Reference antibody#l in a similar way to wild-type B7-H1, excepted B7H1 D122E mutant which binds those 2 antibodies less efficiently. Those three residues are specifics to the 2.7A40PT mAb binding epitope and are not shared by the 2.14H90PT or the Reference antibody#l epitopes. Argl 13 is also involved in the 2.7A40PT epitope but to a lesser extend. Replacement by an Ala does not affect the binding to that antibody but a Tyr or Leu mutations lead to a total lost of binding.
  • EXAMPLE 17 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON A MEMORY T-CELL RESPONSE TO SUB-OPTIMAL CONCENTRATIONS OF A
  • PBMCs Peripheral blood monocytes
  • PBMCs Peripheral blood monocytes
  • RPMI 1640 Glutamax I media Glutamax I media
  • pen/strep GBCO,. 15140
  • Human AB Serum Human AB Serum
  • tetanus toxoid (Calbiochem582231) at a density of 1x105 cells per well.
  • anti-B7-Hl antibodies in the IgGl-TM format or isotype control were added at the indicated concentrations and cultures returned to 37°C for a further 2 days, at which point supematants were harvested and analysed by DELFIA for levels of interferon- ⁇ . Enhancement of interferon- ⁇ release by anti-B7-Hl antibodies is shown in Figure 6.
  • Anti-B7-Hl antibodies 2.9D10, 2.7A40PT and 2.14H90PT are able to increase the release of Interferon- ⁇ . This data confirms the ability of 2.9D10, 2.7A40PT and 2.14H90PT to enhance antigen specific T-cell responses.
  • EXAMPLE 18 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON A MEMORY T-CELL RESPONSE TO OPTIMAL CONCENTRATIONS OF A
  • PBMCs Peripheral blood monocytes
  • Ficoll-Paque Plus GE Healthcare 17-1440-03 density gradient centrifugation as per manufacturers instructions. Following isolation cells were resuspended in RPMI 1640 Glutamax I media (GIBCO,.61870) supplemented with 1% pen/strep (GIBCO,.
  • mice The in-vivo activity of anti-human B7-H1 antibodies was investigated in xenograft mouse models using immunocompromised NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice.
  • the mice were engrafted subcutaneously (SC) with human cancer cell lines expressing human B7-H1 and human CD4+ and CD8+ T cells that were isolated from peripheral blood mononuclear cells of healthy donors and cultured to enrich for alloreactive effector T cells.
  • Intraperiteneal (IP) doses of anti-human B7-H1 antibodies were given to mice inoculated with the human pancreatic cancer cell line HP AC or the human melanoma cell line A375.
  • Enriched CD4+ and CD8+ T cells were cultured separately for 7- 10 days in medium supplemented with rhIL-2 and each combined with mitomyosin C treated A375 or HP AC cells. T cells were collected and separately cultured again for 7-10 days in medium supplemented with rhIL-2 and combined with mitomyosin C treated A375 or HPAC cells. CD4+ and CD8+ T cells were collected and combined at a 1 : 1 ratio.
  • A375 and HPAC cancer cell lines and PBMC enriched for CD4+ and CD8+ T cells were mixed immediately before subcutaneous (SC) administration at the indicated effector-to-target (E:T) ratios.
  • the inoculation number of cells for each cancer cell line was predetermined by empirical tumor forming dose studies; in general, 2.5 x 10 6 cells in a total volume of 0.2 mL were engrafted into each animal.
  • IgGlTM isotype control human IgG2a or IgGlOPT (also referred to herein as "IgGlTM") antibody or the anti- B7-H1 antibodies 2.14H9 IgG2a, 2.14H90PT, 2.7A40PT or Reference antibody#l in the IgGlOPT format.
  • IgGlTM isotype control human IgG2a or IgGlOPT
  • Anti-B7-H1 antibodies 2.14H9 IgG2a, 2.14H90PT, 2.7A40PT or Reference antibody#l in the IgGlOPT format.
  • the first dose (200 ⁇ ) of test article was administered IP 1 hour after engraftment of cancer/effector T cells; the animals received up to 4 additional doses of the test article on study days 3, 5, 8 and/or 10.
  • rhIL-2 was administered IP 1 hour after engraftment of cancer/effector T cells; the animals received 4 additional daily doses of rhIL-2 for 4 consecutive days.
  • the formation of tumor was observed in each animal one or two times a week. Tumors were measured by caliper; tumor volumes (V) were calculated using the following formula:
  • TGI tumor growth inhibition
  • % TGI [1 - (mean tumor V of treatment group) ⁇ (mean tumor V of control group)] x 100.
  • Table 26 Study 1 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
  • anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of HPAC (pancreas) cancer cells at day 30 by up to 60%> as compared to the isotype control group ( Figure 10 and Table 28).
  • Table 28 Study 3 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
  • Table 29 Study 4 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
  • IP administration of 2.14H9 IgG2a or 2.70PT anti-B7-Hl antibodies in the A375 (melanoma) xenograft model also significantly inhibited tumor growth at day 29 by as much as 64% and 61% respectively as compared to the isotype control group ( Figure 12 and Table 30).
  • Table 30 Study-5. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies
  • anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 77% as compared to the isotype control group ( Figure 13 and Table 31).
  • Table 31 Study-6. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies Group Test Article Dose (mg/kg/mouse) % TGI at day 25
  • anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 82% as compared to the isotype control group ( Figure 14 and Table 32).
  • anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 93% as compared to the isotype control group ( Figure 15 and Table 33).
  • Table 33 Study-8. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies

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Abstract

Human monoclonal antibodies directed against B7-H1 and uses of these antibodies in diagnostics and for the treatment of diseases associated with the activity and/or expression of B7-H1 are disclosed. Additionally, hybridomas or other cell lines expressing such antibodies are disclosed.

Description

TARGETED BINDING AGENTS AGAINST B7-H1
Field of the Invention
The invention relates to targeted binding agents against the B7-H1 protein and uses of such agents. In some embodiments, the invention relates to fully human monoclonal antibodies directed to B7-H1 and uses of these antibodies. Aspects of the invention also relate to cell lines expressing such targeted binding agents or antibodies. The described targeted binding agents are useful as diagnostics and for the treatment of diseases associated with the activity and/or expression of B7-H1. Description of the Related Art
An adaptive immune response involves activation, selection, and clonal proliferation of two major classes of lymphocytes termed T cells and B cells. After encountering an antigen, T cells proliferate and differentiate into antigen-specific effector cells, while B cells proliferate and differentiate into antibody-secreting cells. T cell activation is a multi-step process requiring several signaling events between the T cell and an antigen-presenting cell (APC). For T cell activation to occur, two types of signals must be delivered to a resting T cell. The first type is mediated by the antigen-specific T cell receptor (TcR), and confers specificity to the immune response. The second, costimulatory, type regulates the magnitude of the response and is delivered through accessory receptors on the T cell.
A primary costimulatory signal is delivered through the activating CD28 receptor upon engagement of its ligands B7-1 or B7-2. In contrast, engagement of the inhibitory CTLA-4 receptor by the same B7-1 or B7-2 ligands results in attenuation of a T cell response. Thus, CTLA-4 signals antagonize costimulation mediated by CD28. At high antigen concentrations, CD28 costimulation overrides the CTLA-4 inhibitory effect. Temporal regulation of the CD28 and CTLA-4 expression maintains a balance between activating and inhibitory signals and ensures the development of an effective immune response, while safeguarding against the development of autoimmunity.
Molecular homologues of CD28 and CTLA-4 and their B-7 like ligands have been recently identified. ICOS is a CD28-like costimulatory receptor. PD-1 (Programmed Death 1) is an inhibitory receptor and a counterpart of CTLA-4. This disclosure relates to modulation of immune responses mediated by B7-H1. B7-H1, also known as PD-L1, is a type I transmembrane protein of approximately 53kDa in size. In humans B7-H1 is expressed on a number of immune cell types including activated and anergic/exhausted T cells, on na'ive and activated B cells, as well as on myeloid dendritic cells (DC), monocytes and mast cells. It is also expressed on non-immune cells including islets of the pancreas, Kupffer cells of the liver, vascular endothelium and selected epithelia, for example airway epithelia and renal tubule epithelia, where its expression is enhanced during inflammatory episodes. B7-H1 expression is also found at increased levels on a number of tumours including, but not limited to breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), and pancreatic cancer, as well as melanoma.
B7-H1 is a member of the B7 family of proteins, which contain two extracellular Ig domains, one N-terminal V-type domain followed by a C-type domain. The intracellular domain of 30 amino acids length contains no obvious signaling motifs, but does bear a potential site for protein kinase C phosphorylation. The murine form of B7-H1 bears 69% amino acid identity with the human form of B7-H1, and also shares a conserved structure.
B7-H1 is known to bind two alternative ligands, the first of these, PD-1, is a 50-55 kDa type I transmembrane receptor that was originally identified in a T cell line undergoing activation-induced apoptosis. PD-1 is expressed on activated T cells, B cells, and monocytes, as well as other cells of the immune system and binds both B7-H1 (PD-L1) and the related B7-DC (PD-L2). The second is the B7 family member B7-1, which is expressed on activated T cells, B cells, monocytes and antigen presenting cells.
PD-1 is a member of the immunoglobulin (Ig) superfamily that contains a single Ig V-like domain in its extracellular region. The PD-1 cytoplasmic domain contains two tyrosines, with the most membrane-proximal tyrosine (VAYEEL in mouse PD-1) located within an ITIM (immuno- receptor tyrosine-based inhibitory motif). The presence of an ITIM on PD-1 indicates that this molecule functions to attenuate antigen receptor signaling by recruitment of cytoplasmic phosphatases. Human and murine PD-1 proteins share about 60% amino acid identity with conservation of four potential N-glycosylation sites, and residues that define the Ig-V domain. The ITIM in the cytoplasmic region and the ITIM-like motif surrounding the carboxy-terminal tyrosine (TEYATI in human and mouse) are also conserved between human and murine orthologues. Signalling via the PD-1/B7-H1 axis is believed to serve critical, non-redundant functions within the immune system, by negatively regulating T cell responses. This regulation is involved in T cell development in the thymus, in regulation of chronic inflammatory responses and in maintenance of both peripheral tolerance and immune privilege. The critical nature of these functions is exemplified in PD-1 -deficient mice, which exhibit an autoimmune phenotype. PD-1 deficiency in the C57BL/6 mice results in chronic progressive lupus-like glomerulonephritis and arthritis. In Balb/c mice, PD-1 deficiency leads to severe cardiomyopathy due to the presence of heart-tissue-specific self-reacting antibodies. The function of signaling via B7-H1/B7-1 is less clear, but is thought to also be involved in delivering negative regulatory signals to both T cells and antigen presenting cells.
B7-H1 expression on tumour cells is believed to aid tumours in evading detection and elimination by the immune system. B7-H1 functions in this respect via several alternative mechanisms including driving exhaustion and anergy of tumour infiltrating T lymphocytes, stimulating secretion of immune repressive cytokines into the tumour micro-environment, stimulating repressive regulatory T cell function and protecting B7-H1 expressing tumour cells from lysis by tumour cell specific cytotoxic T cells.
In general, a need exists to provide safe and effective therapeutic methods for disorders associated with repression of an immune response such as, for example cancer and chronic viral infection. Modulation of the immune responses involved in these disorders can be accomplished by manipulation of the B7-H1/PD-1 pathway.
Summary of the Invention
The present invention relates to targeted binding agents that specifically bind to B7-H1 and inhibit the biological activity of B7-H1. In one embodiment of the invention, the invention relates to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 activity. In another embodiment of the invention, the invention relates to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding of B7-H1 to PD-1. In yet another embodiment of the invention, the invention relates to targeted binding agents that block B7-H1 induced T-cell suppression and thereby enhance anti-tumor immunity. In yet another embodiment of the invention, the invention further relates to targeted binding agents that can further stimulate one or more of the following activities including T cell proliferation, IFN-γ and/or IL-2 secretion in mixed lymphocyte reactions. Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit the biological activity of B7- Hl . In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the biological activity than would occur in the absence of the targeted binding agent.
Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 activity. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 activity than would occur in the absence of the targeted binding agent.
Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding to PD-1. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1/PD-1 receptor ligand binding compared to what would occur in the absence of the targeted binding agent.
In another embodiment, the targeted binding agents of the invention can inhibit binding of PD-l/Fc to human B7-H1 expressed on ES-2 cells. In one embodiment the targeted binding agent inhibits binding with an IC50 of less than 1 nM, 0.5 nM, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07 or 0.06 nM. Further, in another embodiment, the antibodies of the invention have an IC50 of about 1 nM down to about 0.06 nM; or of about 0.5 nM down to about 0.06 nM; or of about 0.1 nM down to about 0.06 nM; or of about 1 nM down to about 0.1 nM; or of about 1 nM down to about 0.5 nM.
Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding to its ligand B7-1. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 95%, 96%, 97%, 98% 99% or 100% of B7-H1/B7-1 receptor ligand binding compared to what would occur in the absence of the targeted binding agent.
Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit B7-H1 induced tumor proliferation. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 induced tumor proliferation than would occur in the absence of the targeted binding agent.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 induced tumor cell survival. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%>, at least 15%, at least 20%>, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 induced tumor cell survival than would occur in the absence of the targeted binding agent.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit tumour growth of A375 or HPAC cancer cell lines. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%), or at least 95% of growth of cancer cells at day 30 compared to an isotype control.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 mediated suppression of tumour reactive T-cells, thereby enhancing anti-tumour cytolytic T-cell activity. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 mediated suppression of tumour reactive T-cell activity than would occur in the absence of the targeted binding agent.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby enhance anti-tumour immunity. In one embodiment the targeted binding agent enhances at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of antitumor immunity than would occur in the absence of the targeted binding agent.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit cell proliferation. In one embodiment the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of cell proliferation than would occur in the absence of the targeted binding agent.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and increase specific cytolytic (CTL) activity against B7-H1 expressing tumor cells. In one embodiment, the antibodies of the invention have an EC50 of less than or equal to 100 nM, 50 nM or 1 nM. Further, in another embodiment, the antibodies of the invention have an EC50 of about 100 nM down to about 1 nM; or of about 50 nM down to about 1 nM; or of about 20 nM down to about 1 nM; or of about 100 nM down to about 50 nM; or of about 100 nM down to about 70 nM.
Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit B7-H1 mediated suppression of T-cell proliferation at an EC50 less than or equal to 100 nM. In one embodiment, the antibodies of the invention have an EC50 of less than or equal to 100 nM, e.g., 90, 80, 70, 60, 50, 40, 30, 20 or 10 nM. Further, in another embodiment, the antibodies of the invention have an EC50 of about 100 nM down to about 10 nM; or of about 50 nM down to about 10 nM; or of about 20 nM down to about 10 nM; or of about 100 nM down to about 50 nM; or of about 100 nM down to about 70 nM; or of about 100 nM down to about 80 nM.
The targeted binding agents also inhibit tumour cell adhesion, motility, invasion and cellular metastasis and in addition, the targeted binding agents are useful for reducing tumour growth. Mechanisms by which this can be achieved can include, and are not limited to, inhibiting B7-H1 activity.
In one embodiment of the invention, the targeted binding agent is an antibody. In one embodiment of the invention, the targeted binding agent is a monoclonal antibody. In one embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody or a fragment thereof. Such monoclonal antibodies may be referred to herein as anti-B7-Hl antibodies or antibodies of the invention.
Antibodies, monoclonal antibodies and human monoclonal antibodies include the antibodies of the IgGl, IgG2, IgG3 and IgG4 isotypes, for example IgG2. In one embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody of the IgG2 isotype. This isotype has reduced potential to elicit effector function in comparison with other isotypes, which may lead to reduced toxicity. In another embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody of the IgGl isotype. The IgGl isotype has increased potential to elicit Antibody Directed Cell-mediated Cytotoxicity (ADCC) in comparison with other isotypes, which may lead to improved efficacy. The IgGl isotype has improved stability in comparison with other isotypes, e.g. IgG4, which may lead to improved bioavailability/ease of manufacture/longer half-life. In one embodiment, the fully human monoclonal antibody of the IgGl isotype is of the z, za or f allotype. In one embodiment of the invention, the targeted binding agent has desirable therapeutic properties, selected from one or more of the following: high binding affinity for B7-H1, the ability to inhibit B7-H1 activity in vitro and in vivo, the ability to inhibit B7-H1 -mediated tumour cell survival, and the ability to inhibit B7-H1 mediated suppression of tumour reactive T-cells, which may in turn reduce tumour cell proliferation, motility, invasion, metastasis, and tumour growth.
In one embodiment, the invention includes antibodies that specifically bind to B7-H1 with very high affinities (Kd). In some embodiments of the invention, the targeted binding agent binds B7-H1 with a binding affinity (Kd) of less than 5 nanomolar (nM). In other embodiments, the targeted binding agent binds with a Kd of less than 4 nM, 3 nM, 2.5nM, 2 nM or 1 nM. Further, in some other embodiments antibodies of the invention binds B7-H1 with a Kd of about 5 nM to about 1 nM; or about 5 nM to about 2 nM; or about 5 nM to about 3 nM; or about 5 nM to about 4 nM; or about 3 nM to about 1 nM; or about 2 nM to about 1 nM. In some embodiments of the invention, the targeted binding agent binds B7-H1 with a Kd of less than 950 picomolar (pM). In some embodiments of the invention, the targeted binding agent binds B7-H1 with a Kd of less than 900 pM. In other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 800 pM, 700 pM or 600 pM. In some embodiments of the invention, the targeted binding agent binds B7-H1 with a Kd of less than 500 pM. In other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 400 pM. In still other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 300 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 200 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 100 pM. Further, in some other embodiments antibodies of the invention binds B7-H1 with a Kd of about 900 pM to about 100 pM; or about 900 pM to about 200 pM; or about 900 pM to about 300 pM; or about 900 pM to about 400 pM; or about 900 pM to about 500 pM; or about 900 pM to about 600 pM; or about 900 pM to about 700 pM; or about 200 pM to about 100 pM; or about 300 pM to about 200 pM; or about 400 pM to about 300 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 90 pM, 80 pM, 70 pM, 60 pM, 55pM or 50pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 60 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 55 pM. Further, in some other embodiments antibodies of the invention binds B7-H1 with a Kd of about 100 pM to about 50 pM; or about 100 pM to about 70 pM; or about 100 pM to about 80 pM; or about 100 pM to about 90 pM; or about 70 pM to about 50 pM; or about 60 pM to about 50 pM; or about 55 pM to about 50 pM. The Kd may be assessed using a method described herein or known to one of skill in the art (e.g., a BIAcore assay, ELISA) (Biacore International AB, Uppsala, Sweden). Targeted binding agents of the invention have considerably improved binding affinities for B7-H1 in comparison with the antibodies reported in the prior art.
The binding properties of the targeted binding agent or antibody of the invention may also be measured by reference to the dissociation or association rates (k0ff and kon respectively).
In one embodiment of the invention, a targeted binding agent or an antibody of the invention may have a kon rate (antibody (Ab) + antigen (Ag)kon— Ab- Ag) of at least 104 M'V1, at least 5 X 104 M'V1, at least 105 M'V1, at least 2 X 105 M'V1, at least 5 X 105 M'V1, at least 106 M'V1, at least 5 X 106 M'V1, at least 107 M'V1, at least 5 X 107 M'V1, or at least 108 M'V1 as measured by a BIAcore assay. Further, in some other embodiments antibodies of the invention have a kon rate of about 5 X 104 M'V1 to about 5 X 108 M'V1 ; or of about 5 X 105 M"V 1 to about 5 X 108 M'V1; or of about 5 X 106 M'V1 to about 5 X 108 M'V1; or of about 5 X 107 M'V1 to about 5 X 108 M'V1, as measured by a BIAcore assay. In another embodiment of the invention, targeted binding agent or an antibody may have a k0ff rate ( (Ab-Ag)ko → antibody (Ab) + antigen (Ag)) of less than 5x10"1 s"1, less than 10"1 s"1,
2 1 2 1 3 1 3 1 4 1 less than 5x10" s" , less than 10" s" , less than 5x10" s" , less than 10" s" , less than 5x10" s" , less than 10"4 s"1, less than 5xl0"5 s"1, less than 10"5 s"1, less than 5xl0"6 s"1, less than 10"6 s"1, less than 5xl0"7 s"1, less than 10"7 s"1, less than 5xl0"8 s"1, less than 10"8 s"1, less than 5xl0"9 s"1, less than 10"9 s"1, or less than 10"10 s"1 as measured by a BIAcore assay. Further, in some other embodiments antibodies of the invention have a k0ff rate of about 1 X 10"4 s"1 to about 1 X 10"5 s"1; or of about 1 X 10"4 s"1 to about 5 X 10"4 s"1 ,as measured by a BIAcore assay.
The targeted binding agent of the invention specifically binds human B7-H1. In some examples, the targeted binding agent of the invention does not bind other immune co-modulatory proteins, e.g., human PD-L2, human B7-H2, human B7-H3, human CD28, human CTLA-4 and human PD1.
In another embodiment, the targeted binding agent of the invention is cross-reactive with other B7-H1 proteins from other species. In one embodiment, the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1. In another embodiment, the targeted binding agent of the invention is cross-reactive with mouse B7-H1, e.g., 2.7A4. In another embodiment, the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1 and with mouse B7-H1, e.g., 2.7A4. In another embodiment, the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1 but not with mouse B7- Hl, e.g., 2.9D10 and 2.14H9.
In one embodiment, the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences (VH) shown in Table 8. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT. Light-chain promiscuity is well established in the art, thus, a targeted binding agent or antibody comprising a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT, or another antibody as disclosed herein, may further comprise any one of the light chain sequences (VL) shown in Table 9 or of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT or 2.14H90PT, or other antibody as disclosed herein. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT and further comprising the corresponding light chain sequence of antibody 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT. In some embodiments, the antibody is a fully human monoclonal antibody.
In one embodiment, the targeted binding agent or antibody comprises a sequence comprising any one of the light chain sequences shown in Table 9. In another embodiment, the targeted binding agent or antibody comprises a sequence comprising any one of the light chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.7A4 and further comprising the light chain sequence of antibody 2.7A4. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.14H9 and further comprising the light chain sequence of antibody 2.14H9. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.9D10 and further comprising the light chain sequence of antibody 2.9D10. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.7A.40PT and further comprising the light chain sequence of antibody 2.7A.40PT. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.14H90PT and further comprising the light chain sequence of antibody 2.14H90PT.
In some embodiments, the targeting binding agent is any one of the monoclonal antibodies as shown in Table 1. In some embodiments, the targeting binding agent is a monoclonal antibody selected from the group consisting of: 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT. In one embodiment, the targeted binding agent comprises one or more of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT. In certain embodiments, the targeting binding agent is monoclonal antibody 2.7A4. In certain other embodiments, the targeting binding agent is monoclonal antibody 2.14H9. In still other embodiments, the targeting binding agent is monoclonal antibody 2.9D10. In certain embodiments, the targeting binding agent is monoclonal antibody 2.7A40PT. In certain other embodiments, the targeting binding agent is monoclonal antibody 2.14H90PT. In additional embodiments, the targeted binding agent is derivable from any of the foregoing monoclonal antibodies.
In another embodiment the targeted binding agent may comprise a sequence comprising any one of the CDR1, CDR2 or CDR3 of the heavy chain variable sequences encoded by a polynucleotide in a plasmid designated 2.7A4 G, 2.14H9 G, and 2.9D10 NG which were deposited at NCIMB under number 41598 on November 19, 2008, under number 41597 on November 19, 2008, and under number 41599 on November 19, 2008, respectively.
In another embodiment the targeted binding agent may comprise a sequence comprising any one of the CDR1, CDR2 or CDR3 of the light chain variable domain sequences encoded by a polynucleotide in a plasmid designated 2.7A4 G, 2.14H9 G and 2.9D10 NG which were deposited under number 41598 on November 19, 2008, under number 41597 on November 19, 2008, or under number 41599 on November 19, 2008, respectively.
In one embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008 and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
In one embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
In one embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008, and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19,
2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19,
2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
In one embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In one embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008. In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB number 41598 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under number 41598 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under number 41598 on November 19, 2008 and a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under number 41598 on November 19, 2008. In another embodiment, a targeted binding agent or an antibody of the invention comprises a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008 and a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
In another embodiment, a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
In one embodiment a targeted binding agent or an antibody may comprise a sequence comprising a heavy chain CDR1 (HCDRl), heavy chain CDR2 (HCDR2) and heavy chain CDR3 (HCDR3) selected from any one of the sequences shown in Table 8. In one embodiment a targeted binding agent or an antibody may comprise a sequence comprising a light chain CDR1 (LCDRl), light chain CDR2 (LCDR2) and light chain CDR3 (LCDR3) selected from any one of the sequences shown in Table 9. In one embodiment a targeted binding agent or an antibody may comprise a sequence comprising a HCDRl, HCDR2 and HCDR3 selected from any one of the CDRs of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, or 3.18G1. In one embodiment a targeted binding agent or an antibody may comprise a sequence comprising a LCDRl, LCDR2 and LCDR3 selected from any one of the CDRs of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, or 3.18Gl .
A further embodiment is a targeted binding agent or an antibody that specifically binds to B7-H1 and comprises a sequence comprising one of the CDR2 and one of the CDR3 sequences shown in Table 9. In a further embodiment the targeted binding agent or antibody further comprises a sequence comprising: a CDR3 sequence as shown in Table 8. In a further embodiment the targeted binding agent or antibody further comprises a sequence comprising: a CDR2 and a CDR3 sequence as shown in Table 8 and/or Table 9. In a further embodiment the targeted binding agent or antibody further comprises a sequence comprising: a CDRl, a CDR2 and a CDR3 sequence as shown in Table 8 and/or Table 9.
In another embodiment the targeted binding agent or antibody may comprise a sequence comprising any one of a CDRl, a CDR2 or a CDR3 of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, as shown in Table 8. In another embodiment the targeted binding agent or antibody may comprise a sequence comprising any one of a CDRl, a CDR2 or a CDR3 of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, as shown in Table 9. In one embodiment the targeted binding agent or antibody may comprise a sequence comprising a CDRl, a CDR2 and a CDR3 of any one of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT, as shown in Table 8. In another embodiment the targeted binding agent or antibody may comprise a sequence comprising a CDRl, a CDR2 and a CDR3 of any one of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT, as shown in Table 9.
In another embodiment the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.7A4 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.7A4 as shown in Table 9. In another embodiment the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.14H9 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.14H9 as shown in Table 9. In another embodiment the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.9D10 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.9D10 as shown in Table 9. In some embodiments, the antibody is a fully human monoclonal antibody.
It is noted that those of ordinary skill in the art can readily accomplish CDR determinations. See for example, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. Kabat provides multiple sequence alignments of immunoglobulin chains from numerous species antibody isotypes. The aligned sequences are numbered according to a single numbering system, the Kabat numbering system. The Kabat sequences have been updated since the 1991 publication and are available as an electronic sequence database (presently available from the Kabat Database Website; see also Nucleic Acids Research, 2000, 28(1), 214-218). Any immunoglobulin sequence can be numbered according to Kabat by performing an alignment with the Kabat reference sequence. Accordingly, the Kabat numbering system provides a uniform system for numbering immunoglobulin chains.
A further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT, or as shown in Table 8 or Table 9. A further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 and Table 9. In one embodiment the targeted binding agent or antibody comprises a sequence comprising the contiguous sequences spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences of monoclonal antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 or Table 9. A further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences of monoclonal antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 and Table 9. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment, a targeted binding agent or antibody of the invention comprises a CDR3 sequence as shown in Table 8 or 9; or any one of a CDRl, a CDR2 or a CDR3 sequence as shown in Table 8 or 9; or a CDRl, a CDR2 and a CDR3 sequence of a light chain variable domain sequence as shown in Table 8; or a CDRl, a CDR2 and a CDR3 sequence of a heavy chain variable domain sequence sequence as shown as shown in Table 9.
One embodiment provides a targeted binding agent or antibody, or antigen-binding portion thereof, wherein the agent or antibody, or antigen-binding portion thereof, comprises a sequence comprising SEQ ID NO.:2, SEQ ID NO.:7, SEQ ID NO.: 12, SEQ ID NO.: 17, SEQ ID NO.:22, SEQ ID NO.:27, SEQ ID NO.:32, SEQ ID NO.:37, SEQ ID NO.:42, SEQ ID NO.:47, SEQ ID NO.:52, SEQ ID NO.:57, SEQ ID NO.:62, SEQ ID NO.:67, SEQ ID NO.:72, or SEQ ID NO.:77.
One embodiment provides a targeted binding agent or antibody, or antigen-binding portion thereof, wherein the agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:2. In one embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:7. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:2 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:7.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.: 12. In one embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.: 17. In some embodiments, the antibody is a fully human monoclonal antibody.
In one embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 12 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 17.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:22. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:27. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:22 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:27. In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:32. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:37. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:32 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:37.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:42. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:47. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:42 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:47.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:52. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:57. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:52 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:57.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:62. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:67. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 62 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 67.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.: 72. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:77. In some embodiments, the antibody is a fully human monoclonal antibody.
In another embodiment the targeted binding agent or antibody, or antigen-binding portion thereof, comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 72 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 77.
In one embodiment, the targeted binding agent or antibody comprises variants or derivatives of the CDRs disclosed herein, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3), the light or heavy chain sequences disclosed herein, or the antibodies disclosed herein. Variants include targeted binding agents or antibodies comprising sequences which have as many as twenty, sixteen, ten, nine or fewer, e.g. one, two, three, four, five or six amino acid additions, substitutions, deletions, and/or insertions in any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein. Variants include targeted binding agents or antibodies comprising sequences which have one, two or three, amino acid additions, substitutions, deletions, and/or insertions in any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein. Variants include targeted binding agents or antibodies comprising sequences which have at least about 60, 70, 80, 85, 90, 95, 98 or about 99% amino acid sequence identity with any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FR1 through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein. The percent identity of two amino acid sequences can be determined by any method known to one skilled in the art, including, but not limited to, pairwise protein alignment. In one embodiment variants comprise changes in the CDR sequences or light or heavy chain sequences disclosed herein that are naturally occurring or are introduced by in vitro engineering of native sequences using recombinant DNA techniques or mutagenesis techniques. Naturally occurring variants include those which are generated in vivo in the corresponding germline nucleotide sequences during the generation of an antibody to a foreign antigen.
In one embodiment variants include targeted binding agents or antibodies comprising sequences which have (a) a VH CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 3;
(b) a VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 4;
(c) a VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 5;
(d) a VL CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to VL CDRl of SEQ ID NO: 8;
(e) a VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 9; and
(f) a VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 10.
In another embodiment, variants include targeted binding agents or antibodies comprising sequences which have (a) a VH CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 23;
(b) a VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 24; (c) a VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 25;
(d) a VL CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to VL CDR1 of SEQ ID NO: 28;
(e) a VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 29; and
(f) a VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 30.
In one embodiment the derivative may be a heteroantibody, that is an antibody in which two or more antibodies are linked together. Derivatives include antibodies which have been chemically modified. Examples include covalent attachment of one or more polymers, such as water-soluble polymers, N-linked, or O-linked carbohydrates, sugars, phosphates, and/or other such molecules. The derivatives are modified in a manner that is different from naturally occurring or starting antibody, either in the type or location of the molecules attached. Derivatives further include deletion of one or more chemical groups which are naturally present on the antibody.
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one, any two, any three, any four or all five of the germline residues as indicated in Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 10.
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7, wherein SEQ ID NO.: 7 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11 and any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7, wherein SEQ ID NO.: 7 comprises any one, any two, any three, any four, any five, for all five of the germline residues as indicated in Table 11.
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12, wherein SEQ ID NO.: 12 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 12. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12, wherein SEQ ID NO.: 12 comprises any one, any two or all two of the germline residues as indicated in Table 12.
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17, wherein SEQ ID NO.: 17 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 13. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17, wherein SEQ ID NO.: 17 comprises any one, any two, any three, any four or all four of the germline residues as indicated in Table 13.
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27, wherein SEQ ID NO.: 27 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 14. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27, wherein SEQ ID NO.: 27 comprises any one, any two, any three or all three of the germline residues as indicated in Table 14.
A further embodiment of the invention is a targeted binding agent or antibody which competes for binding to B7-H1 with the targeted binding agent or antibodies of the invention. In another embodiment of the invention there is an antibody which competes for binding to B7-H1 with the targeted binding agent or antibodies of the invention. In another embodiment the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT. "Competes" indicates that the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT, i.e. competition is unidirectional.
Embodiments of the invention include a targeted binding agent or antibody which cross competes with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT for binding to B7-H1. "Cross competes" indicates that the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT, and vice versa, i.e. competition is bidirectional.
A further embodiment of the invention is a targeted binding agent or antibody that binds to the same epitope or epitopes on the extracellular domain of human B7-H1 as the targeted binding agent or antibodies of the invention. Embodiments of the invention also include a targeted binding agent or antibody that binds to the same epitope or epitopes on the extracellular domain of human B7-H1 as any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
In one embodiment, the targeted binding agent or antibody binds an epitope on human
B7-H1 including at least one or more of the following amino acids selected from the group consisting of Asp at position 122 and Arg at position 125. In another embodiment, an antibody of the invention binds an epitope on human B7-H1 comprising at least two of the following three amino acid residues of Asp at position 122, Arg at position 125 and Arg at position 113. In another embodiment, the antibody binds an epitope on human B7-H1, wherein the antibody exhibits no binding to He at position 54, Ser at position 117 and Ala at position 121 on human B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Arg at position 113 is mutated to an Ala, or to a Tyr, or to a Leu as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Arg at position 125 is mutated to an Ala, or to a Gin, or to a Ser as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention retains its ability to bind to human B7-H1 if the Arg at position 123 is mutated to an Ala, or to a Phe, or to a Thr as determined by a competition assay as compared to binding to wild-type B7-H1. In this example, the antibody is 2.14H9. In another example, the antibody is 2.14H90PT.
In one embodiment, the targeted binding agent or antibody binds an epitope on the extracellular domain of human B7-H1 comprising at least one or more of the following amino acids Asp at position 122 and Thr at position 20. In one embodiment, the antibody binds at least two of the following three amino acid residues of Phe at position 19, Thr at position 20 and Asp at position 122 on human B7-H1. In another embodiment, the shows no binding to at least one of the following three amino acid residues of He at position 54, Met at position 115, Ser at position 117 and Ala at position 121 on human B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Phe at position 19 is mutated to an Ala, or to a Gly, or to a Ser as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Thr at position 20 is mutated to an Ala, or to a Val, or to a Asp as
determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Asp at position 122 is mutated to an Asn, or to a Glu as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention retains its ability to bind to human B7-H1 if the Arg at position 123 is mutated to an Ala, or to a Phe, or to a Thr as determined by a competition assay as compared to binding to wild-type B7-H1. In one example, the antibody is 2.7A4. In another example, the antibody is 2.7A40PT.
In one embodiment, the targeted binding agent is a bispecific antibody. A bispecific antibody is an antibody that has binding specificity for at least two different epitopes on the same or on different proteins. Methods for making bispecific antibodies are known in the art. (See, for example, Millstein et al, Nature, 305:537-539 (1983); Traunecker et al., EMBO J, 10:3655- 3659 (1991); Suresh et al, Methods in Enzymology, 121 :210 (1986); Kostelny et al., J. Immunol, 148(5): 1547-1553 (1992); Hollinger et al, Proc. Natl Acad. Sci. USA, 90:6444-6448 (1993); Gruber et al, J. Immunol, 152:5368 (1994); U.S. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,81; 95,731,168; 4,676,980; and 4,676,980, WO 94/04690; WO 91/00360; WO 92/200373; WO 93/17715; WO 92/08802; and EP 03089.)
Embodiments of the invention described herein relate to monoclonal antibodies that specifically bind B7-H1 and affect B7-H1 function. Other embodiments relate to fully human antibodies that specifically bind B7-H1 and preparations thereof with desirable properties from a therapeutic perspective, including high binding affinity for B7-H1, high selectivity for inhibition of B7-H1 signaling, low toxicity, the ability to block PD-1 receptor activity, the ability to inhibit B7-H1 -induced tumour cell survival through immune suppression, the ability to inhibit B7-H1 mediated repression of anti-tumour immunity, which may in turn inhibit proliferation or invasion -related diseases include neoplastic diseases, and/or the ability of tumour cells to grow in vitro and in vivo. Still other embodiments relate to a method of repressing B7-H1 -mediated T cell inhibition in an animal by administering to an animal in need thereof an effective amount of a composition comprising the antibodies of the invention. Still other embodiments relate to fully human antibodies that specifically bind B7-H1 and preparations thereof that do not result in a significant Human Anti-Chimeric Antibody (HACA) response, thereby allowing for repeated administration.
In one embodiment of the invention there is provided nucleic acid molecule encoding any of the targeted binding agents or antibodies of the invention. In one embodiment is a nucleic acid molecule encoding the light chain or the heavy chain of an antibody of the invention. In one embodiment, the nucleic acid molecule encodes the light chain or the heavy chain of a fully human monoclonal antibody of any of the antibodies described herein. In one embodiment, the nucleic acid molecule encodes the light chain or the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. In another embodiment, the nucleic acid molecule encodes the light chain and the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. The invention also encompasses polynucleotides that hybridize under stringent or lower stringency hybridization conditions, as defined herein, to polynucleotides that encode any of the targeted binding agents or antibodies described herein.
In another embodiment of the invention there is provided a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a targeted binding agent as described hereinabove. In one embodiment of the invention there is provided a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a light chain and/or a heavy chain of an antibody as defined hereinabove. In one embodiment, the vector comprises a nucleic acid molecule encoding the light chain and/or the heavy chain of a fully human monoclonal antibody. In one embodiment, the vector comprises a nucleic acid molecule encoding the light chain or the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. In another embodiment, the vector comprises a nucleic acid molecule encoding the light chain and the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
In a further embodiment there is provided a host cell transformed with any of the nucleic acid molecules as described hereinabove. In another embodiment of the invention there is provided a host cell comprising the vector comprising the nucleic acid molecule as described hereinabove. In one embodiment the host cell may comprise more than one vector.
As known in the art, antibodies can advantageously be, for example, polyclonal, oligoclonal, monoclonal, chimeric, humanised, and/or fully human antibodies.
It will be appreciated that embodiments of the invention are not limited to any particular form of an antibody or method of generation or production. In some embodiments of the invention, the targeted binding agent is a binding fragment of a fully human monoclonal antibody. For example, the targeted binding agent can be a full-length antibody (e.g., having an intact human Fc region) or an antibody binding fragment (e.g., a Fab, Fab' or F(ab')2, Fv, dAb or other well known antibody fragment, as described in more detail below). In addition, the antibodies can be single-domain antibodies such as camelid or human single VH or VL domains that bind to B7-H1, such as a dAb fragment.
Embodiments of the invention described herein also provide cells for producing these antibodies. Examples of cells include hybridomas, or recombinantly created cells, such as Chinese hamster ovary (CHO) cells, variants of CHO cells (for example DG44) and NSO cells that produce antibodies against B7-H1. Additional information about variants of CHO cells can be found in Andersen and Reilly (2004) Current Opinion in Biotechnology 15, 456-462 which is incorporated herein in its entirety by reference. The antibody can be manufactured from a hybridoma that secretes the antibody, or from a recombinantly engineered cell that has been transformed or transfected with a gene or genes encoding the antibody. In addition, one embodiment of the invention is a method of producing a targeted binding agent or an antibody of the invention by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the targeted binding agent or antibody followed by recovery of the targeted binding agent or antibody. In one embodiment is a method of producing an antibody of the invention by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the antibody, followed by recovery of the antibody. Still other embodiments include an antibody of the invention produced by the method of culturing a host cell which expresses an antibody encoded by a nucleic acid molecule encoding an antibody of the invention, and isolating said antibody from said culture.
It should be realised that embodiments of the invention also include any nucleic acid molecule which encodes an antibody or fragment of an antibody of the invention including nucleic acid sequences optimised for increasing yields of antibodies or fragments thereof when transfected into host cells for antibody production.
A further embodiment herein includes a method of producing antibodies that specifically bind to B7-H1 and inhibit the biological activity of B7-H1, by immunising a mammal with cells expressing B7-H1, isolated cell membranes containing B7-H1, purified B7-H1, or a fragment thereof, and/or one or more orthologous sequences or fragments thereof.
A further embodiment herein includes a method of producing high affinity antibodies that specifically bind to B7-H1 and inhibit the biological activity of B7-H1, by immunising a mammal with cells expressing B7-H1, isolated cell membranes containing B7-H1, purified B7- Hl, or a fragment thereof, and/or one or more orthologous sequences or fragments thereof.
Other embodiments are based upon the generation and identification of isolated antibodies that bind specifically to B7-H1 and inhibit the biological activity of B7-H1. B7-H1 is expressed on a number of tumour types. Antibodies that specifically bind to B7-H1 can prevent B7-H1 -mediated tumour cell survival and inhibit B7-H1 mediated repression of anti-tumour immune responses through immune suppression, this can in turn reduce tumour cell invasion, metastasis, tumour growth, and other properties.
In addition, the antibody can be manufactured from a hybridoma that secretes the antibody, or from a recombinantly engineered cell that has been transformed or transfected with a gene or genes encoding the antibody. In one embodiment there is a hybridoma that produces the targeted binding agent or antibody of the invention. In one embodiment there is a hybridoma that produces the light chain and/or the heavy chain of an antibody of the invention. In one embodiment the hybridoma may produce a light chain and/or a heavy chain of a fully human monoclonal antibody. In another embodiment, the hybridoma produces the light chain and/or the heavy chain of the fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. Alternatively the hybridoma may produce an antibody that binds to the same epitope or epitopes as fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. Alternatively the hybridoma may produce an antibody that competes for binding to B7-H1 with fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. Alternatively the hybridoma may produce an antibody that cross-competes for binding to B7-H1 with fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
In other embodiments the invention provides compositions, including a targeted binding agent or antibody of the invention or binding fragment thereof, and a pharmaceutically acceptable carrier.
Still further embodiments of the invention include methods of treating a proliferative or invasion-related disease in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for a proliferative or invasion-related disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments, the animal is human. In certain embodiments, the targeted binding agent is a fully human monoclonal antibody. In certain embodiments, the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
Still further embodiments of the invention include methods of inhibiting cell proliferation or invasion -related disease, with a B7-H1 mediated component, in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for proliferation or invasion -related disease, with a B7-H1 mediated component, and administering to said animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments, the animal is human. In certain embodiments, the targeted binding agent is a fully human monoclonal antibody. In certain embodiments, the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
Still further embodiments of the invention include methods of inhibiting tumour cell invasion, cellular metastasis or tumour growth in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for tumour cell, invasion, cellular metastasis or tumour growth, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments, the animal is human. In certain embodiments, the targeted binding agent is a fully human monoclonal antibody. In certain embodiments, the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
Still further embodiments of the invention include methods of treating an animal suffering from a neoplastic disease by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for a neoplastic disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
Still further embodiments of the invention include methods of treating an animal suffering from a non-neoplastic disease by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for a non-neoplastic disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
Still further embodiments of the invention include methods of treating an animal suffering from chronic viral infection by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for chronic viral infection, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
Still further embodiments of the invention include methods of treating an animal suffering from a malignant tumour by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for a malignant tumour, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
Still further embodiments of the invention include methods of treating an animal suffering from a disease or condition associated with B7-H1 expression by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention. In certain embodiments the method further comprises selecting an animal in need of treatment for a disease or condition associated with B7-H1 expression, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
A malignant tumour may be selected from the group consisting of: solid tumours such as melanoma, skin cancers, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, gallbladder cancer, thyroid tumour, bone cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, testicular cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, renal cell carcinoma, colon cancer, colorectal, pancreatic cancer, esophageal carcinoma, brain/CNS cancers, head and neck cancers, neuronal cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma, sarcomas, cancer of the pleural/peritoneal membranes and leukaemia, including acute myeloid leukaemia, acute lymphoblastic leukaemia, and multiple myeloma.
Treatable proliferative or invasion -related diseases include neoplastic diseases, such as, melanoma, skin cancer, small cell lung cancer, non-small cell lung cancer, salivary gland, glioma, hepatocellular (liver) carcinoma, gallbladder cancer, thyroid tumour, bone cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, testicular cancer, bladder cancer, lung cancer, glioblastoma, thyroid cancer, endometrial cancer, kidney cancer, colon cancer, colorectal cancer, pancreatic cancer, esophageal carcinoma, brain/CNS cancers, neuronal cancers, head and neck cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma, sarcomas, cancer of the pleural/peritoneal membranes and leukaemia, including acute myeloid leukaemia, acute lymphoblastic leukaemia, and multiple myeloma. Treatable chronic viral infections include HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) in humans, simian immunodeficiency virus (SIV) in monkeys, and lymphocytic choriomeningitis virus (LCMV) in mice.
Disease-related cell invasion and/or proliferation may be any abnormal, undesirable or pathological cell invasion and/or proliferation, for example tumour-related cell invasion and/or proliferation.
In one embodiment, the neoplastic disease is a solid tumour selected from any one of the following carcinomas of the breast, colon, colorectal, prostate, stomach, gastric, ovary, esophagus, pancreas, gallbladder, non-small cell lung cancer, thyroid, endometrium, head and neck, renal, renal cell carcinoma, bladder and gliomas.
In one embodiment the present invention is suitable for use in inhibiting B7-H1, in patients with a tumour which is dependent alone, or in part, on B7-H1.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a proliferative or invasion-related disease. In certain embodiments the use further comprises selecting an animal in need of treatment for a proliferative or invasion-related disease.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of medicament for the treatment of proliferation or invasion -related disease, with a B7-H1 mediated component, in an animal. In certain embodiments the use further comprises selecting an animal in need of treatment for proliferation or invasion -related disease, with a B7-H1 mediated component.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of medicament for the treatment of tumour cell invasion, cellular metastasis or tumour growth in an animal. In certain embodiments the use further comprises selecting an animal in need of treatment for tumour cell invasion, cellular metastasis or tumour.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a neoplastic disease. In certain embodiments the use further comprises selecting an animal in need of treatment for a neoplastic disease.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a disease where the etiology is associated with an infectious agent, such as, for example, hepatocellular cancer, gastric cancer, or cervical cancer. In certain embodiments the use further comprises selecting an animal in need of treatment for a neoplastic disease.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a non-neoplastic disease. In certain embodiments the use further comprises selecting an animal in need of treatment for a non-neoplastic disease.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from chronic viral infection. In certain embodiments the use further comprises selecting an animal in need of treatment for a non-neoplastic disease. In still other embodiments, the use further comprises ocular disease, inflammatory disease, cardiovascular disease and sepsis.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a malignant tumour. In certain embodiments the use further comprises selecting an animal in need of treatment for a malignant tumour.
Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a disease or condition associated with B7-H1 expression. In certain embodiments the use further comprises selecting an animal in need of treatment for a disease or condition associated with B7-H1 expression.
Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from a proliferative or invasion-related disease.
Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from tumour cell invasion, cellular metastasis or tumour growth in an animal.
Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from a disease or condition associated with B7-H1 expression.
In one embodiment treatment of a proliferative or invasion-related disease;
a neoplastic disease;
a non-neoplastic disease;
a malignant tumour; or
chronic viral infection; or
a disease or condition associated with B7-H1 expression,
comprises managing, ameliorating, preventing, any of the aforementioned diseases or conditions.
In one embodiment treatment of a neoplastic disease comprises inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, increased time to tumour recurrence, slowing of disease progression.
In one embodiment treatment of a disease or condition associated with B7-H1 expression comprises inhibiting the growth of cells that express B7-H1.
In some embodiments, following administration of the targeted binding agent or antibody of the invention, a clearing agent is administered, to remove excess circulating antibody from the blood.
In some embodiments of the invention, the animal to be treated is a human.
In some embodiments of the invention, the targeted binding agent is a fully human monoclonal antibody.
In some embodiments of the invention, the targeted binding agent is selected from the group consisting of fully human monoclonal antibodies 2.7A4, 2.14H9 and 2.9D10.
Embodiments of the invention include a conjugate comprising the targeted binding agent as described herein, and a therapeutic agent. In some embodiments of the invention, the therapeutic agent is a toxin. In other embodiments, the therapeutic agent is a radioisotope. In still other embodiments, the therapeutic agent is a pharmaceutical composition.
In another aspect, a method of selectively killing a cancerous cell in a patient is provided. The method comprises administering a fully human antibody conjugate to a patient. The fully human antibody conjugate comprises an antibody that can bind to B7-H1 and an agent. The agent is either a toxin, a radioisotope, or another substance that will kill a cancer cell. The antibody conjugate thereby selectively kills the cancer cell. In one aspect, a conjugated fully human antibody that specifically binds to B7-H1 is provided. Attached to the antibody is an agent, and the binding of the antibody to a cell results in the delivery of the agent to the cell. In one embodiment, the above conjugated fully human antibody binds to an extracellular domain of B7-H1. In another embodiment, the antibody and conjugated toxin are internalised by a cell that expresses B7-H1. In another embodiment, the agent is a cytotoxic agent. In another embodiment, the agent is, for example saporin, or auristatin, pseudomonas exotoxin, gelonin, ricin, calicheamicin or maytansine -based immunoconjugates, and the like. In still another embodiment, the agent is a radioisotope.
The targeted binding agent or antibody of the invention can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drugs or radiation therapy or therapeutic vaccines. For example, a monoclonal, oligoclonal or polyclonal mixture of B7-H1 antibodies that block B7-H1 mediated repression of anti-tumour immunity can be administered in combination with a drug shown to inhibit tumour cell proliferation.
According to another aspect of the invention there is provided a pharmaceutical composition comprising a targeted binding agent of antibody of the invention and a pharmaceutically acceptable carrier.
Another embodiment of the invention includes a method of diagnosing diseases or conditions in which an antibody as disclosed herein is utilised to detect the presence and/or level of B7-H1 in a patient or patient sample. In one embodiment, the patient sample is blood or blood serum or urine. In further embodiments, methods for the identification of risk factors, diagnosis of disease, and staging of disease is presented which involves the identification of the expression and/or overexpression of B7-H1 using anti-B7-Hl antibodies. In some embodiments, the methods comprise administering to a patient a fully human antibody conjugate that selectively binds to B7-H1 on a cell. The antibody conjugate comprises an antibody that specifically binds to B7-H1 and a label. The methods further comprise observing the presence of the label in the patient. A relatively high amount of the label will indicate a relatively high risk of the disease and a relatively low amount of the label will indicate a relatively low risk of the disease. In one embodiment, the label is a green fluorescent protein.
The invention further provides methods for assaying for the presence and/or level of B7- HI in a patient sample, comprising contacting an antibody as disclosed herein with a biological sample from a patient, and detecting the level of binding between said antibody and B7-H1 in said sample. In more specific embodiments, the biological sample is blood, plasma or serum.
Another embodiment of the invention includes a method for diagnosing a condition associated with the expression of B7-H1 in a cell by contacting the serum or a cell with an antibody as disclosed herein, and thereafter detecting the presence of B7-H1. In one embodiment the condition can be a proliferative or invasion -related disease including, but not limited to, a neoplastic disease.
In another embodiment, the invention includes an assay kit for detecting B7-H1 in mammalian tissues, cells, or body fluids. Such a kit would be useful to screen for B7-H1 -related diseases. The kit includes a targeted binding agent or antibody of the invention and a means for indicating the reaction of the targeted binding agent or antibody with B7-H1, if present. In one embodiment the antibody is a monoclonal antibody. In one embodiment, the antibody that binds B7-H1 is labeled. In another embodiment the antibody is an unlabeled primary antibody and the kit further includes a means for detecting the primary antibody. In one embodiment, the means for detecting includes a labeled second antibody that is an anti-immunoglobulin. The antibody may be labeled with a marker selected from the group consisting of a fluorochrome, an enzyme, a radionuclide and a radiopaque material.
In some embodiments, the targeted binding agents or antibodies as disclosed herein can be modified to enhance their capability of fixing complement and participating in complement- dependent cytotoxicity (CDC). In other embodiments, the targeted binding agents or antibodies can be modified to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC). In yet other embodiments, the targeted binding agents or antibodies can be modified both to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to enhance their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).
In some embodiments, the targeted binding agents or antibodies as disclosed herein can be modified to reduce their capability of fixing complement and participating in complement- dependent cytotoxicity (CDC). In other embodiments, the targeted binding agents or antibodies can be modified to reduce their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC). In yet other embodiments, the targeted binding agents or antibodies as disclosed herein can be modified both to reduce their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to reduce their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).
In certain embodiments, the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 4 to 7 days. In certain embodiments, the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 2 to 5 days, 3 to 6 days, 4 to 7 days, 5 to 8 days, 6 to 9 days, 7 to 10 days, 8 to 11 days, 8 to 12, 9 to 13, 10 to 14, 11 to 15, 12 to 16, 13 to 17, 14 to 18, 15 to 19, or 16 to 20 days. In other embodiments, the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 17 to 21 days, 18 to 22 days, 19 to 23 days, 20 to 24 days, 21 to 25, days, 22 to 26 days, 23 to 27 days, 24 to 28 days, 25 to 29 days, or 26 to 30 days. In still further embodiments the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention can be up to about 50 days. In certain embodiments, the half-lives of antibodies and of compositions of the invention can be prolonged by methods known in the art. Such prolongation can in turn reduce the amount and/or frequency of dosing of the antibody compositions. Antibodies with improved in vivo half-lives and methods for preparing them are disclosed in U.S. Patent No. 6,277,375; and International Publication Nos. WO 98/23289 and WO 97/3461.
In another embodiment, the invention provides an article of manufacture including a container. The container includes a composition containing a targeted binding agent or antibody as disclosed herein, and a package insert or label indicating that the composition can be used to treat cell adhesion, invasion, angiogenesis, and/or proliferation -related diseases, including, but not limited to, diseases characterised by the expression or overexpression of B7-H1.
In other embodiments, the invention provides a kit for treating diseases involving the expression of B7-H1, comprising a targeted binding agent or antibody as disclosed herein, and instructions to administer the monoclonal antibodies to a subject in need of treatment.
The present invention provides formulation of proteins comprising a variant Fc region. That is, a non naturally occurring Fc region, for example an Fc region comprising one or more non naturally occurring amino acid residues. Also encompassed by the variant Fc regions of present invention are Fc regions which comprise amino acid deletions, additions and/or modifications. The serum half-life of proteins comprising Fc regions may be increased by increasing the binding affinity of the Fc region for FcRn. In one embodiment, the Fc variant protein has enhanced serum half life relative to comparable molecule.
In another embodiment, the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat. Optionally, the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat and at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
In another embodiment, the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 234, 235 and 331 , as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat. In a further specific embodiment, an Fc variant of the invention comprises the 234F, 235F, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat. In another specific embodiment, an Fc variant of the invention comprises the 234F, 235 Y, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat. In another specific embodiment, an Fc variant of the invention comprises the 234F, 235E, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat. Optionally, the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat; at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, and 33 IS, as numbered by the EU index as set forth in Kabat, and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat. As used herein, the "OPT" and "TM" designations are synonymous and are used to describe antibodies of the invention engineered to introduce the three mutations; L234F and L235E in the hinge and P331S in the CH2 domain of the IgG molecule to eliminate its ability to trigger antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity (Oganesyan V. et al. (2008), Acta Cryst., D64: 700-704).
In another embodiment, the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least a non naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat. Optionally, the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
In another embodiment, the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 234, 235 and 331, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat. Optionally, the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat; and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
Methods for generating non naturally occurring Fc regions are known in the art. For example, amino acid substitutions and/or deletions can be generated by mutagenesis methods, including, but not limited to, site-directed mutagenesis (Kunkel, Proc. Natl. Acad. Sci. USA 82:488-492 (1985) ), PCR mutagenesis (Higuchi, in "PCR Protocols: A Guide to Methods and Applications", Academic Press, San Diego, pp. 177-183 (1990)), and cassette mutagenesis (Wells et al, Gene 34:315-323 (1985)). Preferably, site-directed mutagenesis is performed by the overlap-extension PCR method (Higuchi, in "PCR Technology: Principles and Applications for DNA Amplification", Stockton Press, New York, pp. 61-70 (1989)). The technique of overlap- extension PCR (Higuchi, ibid.) can also be used to introduce any desired mutation(s) into a target sequence (the starting DNA). For example, the first round of PCR in the overlap- extension method involves amplifying the target sequence with an outside primer (primer 1) and an internal mutagenesis primer (primer 3), and separately with a second outside primer (primer 4) and an internal primer (primer 2), yielding two PCR segments (segments A and B). The internal mutagenesis primer (primer 3) is designed to contain mismatches to the target sequence specifying the desired mutation(s). In the second round of PCR, the products of the first round of PCR (segments A and B) are amplified by PCR using the two outside primers (primers 1 and 4). The resulting full-length PCR segment (segment C) is digested with restriction enzymes and the resulting restriction fragment is cloned into an appropriate vector. As the first step of mutagenesis, the starting DNA (e.g., encoding an Fc fusion protein, an antibody or simply an Fc region), is operably cloned into a mutagenesis vector. The primers are designed to reflect the desired amino acid substitution. Other methods useful for the generation of variant Fc regions are known in the art (see, e.g., U.S. Patent Nos. 5,624,821; 5,885,573; 5,677,425; 6,165,745; 6,277,375; 5,869,046; 6,121,022; 5,624,821; 5,648,260; 6,528,624; 6,194,551; 6,737,056; 6,821,505; 6,277,375; U.S. Patent Publication Nos. 2004/0002587 and PCT Publications WO 94/29351; WO 99/58572; WO 00/42072; WO 02/060919; WO 04/029207; WO 04/099249; WO 04/063351).
In some embodiments of the invention, the glycosylation patterns of the antibodies provided herein are modified to enhance ADCC and CDC effector function. See Shields RL et al, (2002) JBC. 277:26733; Shinkawa T et al, (2003) JBC. 278:3466 and Okazaki A et al, (2004) J. Mol. Biol., 336: 1239. In some embodiments, an Fc variant protein comprises one or more engineered glycoforms, i.e., a carbohydrate composition that is covalently attached to the molecule comprising an Fc region. Engineered glycoforms may be useful for a variety of purposes, including but not limited to enhancing or reducing effector function. Engineered glycoforms may be generated by any method known to one skilled in the art, for example by using engineered or variant expression strains, by co-expression with one or more enzymes, for example DI N-acetylglucosaminyltransferase III (GnTIl l), by expressing a molecule comprising an Fc region in various organisms or cell lines from various organisms, or by modifying carbohydrate(s) after the molecule comprising Fc region has been expressed. Methods for generating engineered glycoforms are known in the art, and include but are not limited to those described in Umana et al, 1999, Nat. Biotechnol 17: 176-180; Davies et al., 20017 Biotechnol Bioeng 74:288-294; Shields et al, 2002, J Biol Chem 277:26733-26740; Shinkawa et al, 2003, J Biol Chem 278:3466-3473) U.S. Pat. No. 6,602,684; U.S. Ser. No. 10/277,370; U.S. Ser. No. 10/113,929; PCT WO 00/61739A1; PCT WO 01/292246A1; PCT WO 02/311140A1; PCT WO 02/30954A1; Potillegent™ technology (Biowa, Inc. Princeton, N.J.); GlycoMAb™ glycosylation engineering technology (GLYCART biotechnology AG, Zurich, Switzerland). See, e.g., WO 00061739; EA01229125; US 20030115614; Okazaki et al, 2004, JMB, 336: 1239-49.
It is also known in the art that the glycosylation of the Fc region can be modified to increase or decrease effector function (see for examples, Umana et al, 1999, Nat. Biotechnol 17: 176-180; Davies et al, 2001, Biotechnol Bioeng 74:288-294; Shields et al, 2002, J Biol Chem 277:26733-26740; Shinkawa et al, 2003, J Biol Chem 278:3466-3473) U.S. Pat. No. 6,602,684; U.S. Ser. No. 10/277,370; U.S. Ser. No. 10/113,929; PCT WO 00/61739A1; PCT WO 01/292246A1; PCT WO 02/311140A1; PCT WO 02/30954A1; Potillegent™ technology (Biowa, Inc. Princeton, N.J.); GlycoMAb™ glycosylation engineering technology (GLYCART biotechnology AG, Zurich, Switzerland). Accordingly, in one embodiment the Fc regions of the antibodies of the invention comprise altered glycosylation of amino acid residues. In another embodiment, the altered glycosylation of the amino acid residues results in lowered effector function. In another embodiment, the altered glycosylation of the amino acid residues results in increased effector function. In a specific embodiment, the Fc region has reduced fucosylation. In another embodiment, the Fc region is afucosylated (see for examples, U.S. Patent Application Publication No.2005/0226867).
Brief Description Of The Drawings
Fig. 1 is a bar graph showing the effects of the anti-B7-Hl antibodies of the invention on
T cell proliferation in beads assay.
Fig. 2 is a bar graph showing enhancement of T-cell proliferation by anti-B7-Hl antibodies of the invention in DCMLR assay.
Fig. 3 is a bar graph showing IFN-γ release by anti-B7-Hl antibodies of the invention in DCMLR assay.
Fig. 4 is a graph showing 95% confidence interval for anti-B7-Hl IC50 by anti-B7-Hl antibodies of the invention in the human PD1 /human B7-H1 ligand inhibition assay to evaluate the impact of IgG class switching and germlining on antibody activity.
Fig. 5 is a line graph showing the results from an ELISA assay that was performed to evaluate anti-B7-Hl antibodies of the invention cross-reactivity to co-modulatory antigens.
Fig. 6 is a bar graph showing the effects of anti-B7-Hl antibodies of the invention in the in-vitro Tet-recall assay.
Fig. 7 is a bar graph showing the results form testing agonism activity of anti-B7-Hl antibodies of the invention using the Tet-recall assay.
Fig. 8A/B/C are line graphs showing the effect of anti-B7-Hl antibodies of the invention on HPAC cells in a mouse xenograft model.
Fig. 9A/B/C are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
Fig. 10A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on HPAC cells in a mouse xenograft model.
Fig. 11 is a line graph showing the effect of anti-B7-Hl antibodies of the invention on
HPAC cells in a mouse xenograft model. Fig. 12A/B/C/D are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
Fig. 13A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model with and without the presence of T cells.
Fig. 14A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model with and without the presence of T cells.
Fig. 15 is a line graph showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
Definitions
Unless otherwise defined, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures utilised in connection with, and techniques of, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridisation described herein are those well known and commonly used in the art.
Standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See for example, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001)), which is incorporated herein by reference. The nomenclatures utilised in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. As utilised in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
An antagonist or inhibitor may be a polypeptide, nucleic acid, carbohydrate, lipid, small molecular weight compound, an oligonucleotide, an oligopeptide, RNA interference (RNAi), antisense, a recombinant protein, an antibody, or fragments thereof or conjugates or fusion proteins thereof. For a review of RNAi see Milhavet O, Gary DS, Mattson MP. (Pharmacol Rev. 2003 Dec;55(4):629-48. Review) and antisense (see Opalinska JB, Gewirtz AM. (Sci STKE. 2003 Oct 28;2003 (206):pe47.)
A compound refers to any small molecular weight compound with a molecular weight of less than about 2000 Daltons.
The term "B7-H1" refers to the human B7-H, B7H1, B7-H1, B7 homolog 1, CD274 antigen, PDCD1L1, PDCD1LG1, PDCD1 ligand 1, PDL1, PD-L1, Programmed cell death 1 ligand 1 precursor, or Programmed death ligand 1.
The term "neutralising" or "inhibits" when referring to a targeted binding agent, such as an antibody, relates to the ability of said agent to eliminate, reduce, or significantly reduce, the activity of a target antigen. Accordingly, a "neutralising" anti-B7-Hl antibody of the invention is capable of eliminating or significantly reducing the activity of B7-H1. A neutralising, antagonising or inhibiting antibody that specifically binds B7-H1 may, for example, act by blocking the binding of B7-H1 to its cognate ligands. Ideally, a neutralising antibody against B7- HI inhibits B7-H1 mediated repression of T-cell immunity. A neutralising, antagonising or inhibiting antibody that specifically binds B7-H1 may, for example, act by inhibiting binding of B7-H1 to PD-1 and/or to B7-1.
"Inhibiting the biological activity of B7-H1" encompasses an inhibition of B7-H1 activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%), at least 80%>, at least 85%>, at least 90%>, or at least 95%> in comparison with the biological activity in the absence of a targeted binding agent or antibody of the invention.
The term "polypeptide" is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence. Hence, native protein, fragments, and analogs are species of the polypeptide genus. Preferred polypeptides in accordance with the invention comprise the human heavy chain immunoglobulin molecules and the human kappa light chain immunoglobulin molecules, as well as antibody molecules formed by combinations comprising the heavy chain immunoglobulin molecules with light chain immunoglobulin molecules, such as the kappa or lambda light chain immunoglobulin molecules, and vice versa, as well as fragments and analogs thereof. Preferred polypeptides in accordance with the invention may also comprise solely the human heavy chain immunoglobulin molecules or fragments thereof.
The term "naturally occurring" as used herein as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory or otherwise is naturally occurring.
The term "control sequence" as used herein refers to polynucleotide sequences that are necessary either to effect or to affect the expression and processing of coding sequences to which they are connected. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences may include promoters, enhancers, introns, transcription termination sequences, polyadenylation signal sequences, and 5' and '3 untranslated regions. The term "control sequences" is intended to include, at a minimum, all components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
The term "polynucleotide" as referred to herein means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide, or RNA-DNA hetero-duplexes. The term includes single and double stranded forms of DNA.
The term "oligonucleotide" referred to herein includes naturally occurring, and modified nucleotides linked together by naturally occurring, and non naturally occurring linkages. Oligonucleotides are a polynucleotide subset generally comprising a length of 200 bases or fewer. Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in length. Oligonucleotides are usually single stranded, e.g. for probes; although oligonucleotides may be double stranded, e.g. for use in the construction of a gene mutant. Oligonucleotides can be either sense or antisense oligonucleotides. The term "naturally occurring nucleotides" referred to herein includes deoxyribonucleotides and ribonucleotides. The term "modified nucleotides" referred to herein includes nucleotides with modified or substituted sugar groups and the like. The term "oligonucleotide linkages" referred to herein includes oligonucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res. 14:9081 (1986); Stec et al. J. Am. Chem. Soc. 106:6077 (1984); Stein et al. Nucl. Acids Res. 16:3209 (1988); Zon et al. Anti-Cancer Drug Design 6:539 (1991); Zon et al. Oligonucleotides and Analogues: A Practical Approach, pp. 87-108 (F. Eckstein, Ed., Oxford University Press, Oxford England (1991)); Stec et al. U.S. Patent No. 5,151,510; Uhlmann and Peyman Chemical Reviews 90:543 (1990), the disclosures of which are hereby incorporated by reference. An oligonucleotide can include a label for detection, if desired.
The term "selectively hybridise" referred to herein means to detectably and specifically bind. Polynucleotides, oligonucleotides and fragments thereof selectively hybridise to nucleic acid strands under hybridisation and wash conditions that minimise appreciable amounts of detectable binding to nonspecific nucleic acids. High stringency conditions can be used to achieve selective hybridisation conditions as known in the art and discussed herein. Generally, the nucleic acid sequence homology between the polynucleotides, oligonucleotides, or antibody fragments and a nucleic acid sequence of interest will be at least 80%, and more typically with preferably increasing homologies of at least 85%, 90%, 95%, 99%, and 100%.
Stringent hybridization conditions include, but are not limited to, hybridization to filter- bound DNA in 6X sodium chloride/sodium citrate (SSC) (0.9 M NaCl/90 mM NaCitrate, pH 7.0) at about 45°C followed by one or more washes in 0.2X SSC/0.1% SDS at about 50-65°C, highly stringent conditions such as hybridization to filter-bound DNA in 6X SSC at about 45°C followed by one or more washes in 0.1X SSC/0.2%o SDS at about 60°C, or any other stringent hybridization conditions known to those skilled in the art (see, for example, Ausubel, F.M. et al., eds. 1989 Current Protocols in Molecular Biology, vol. 1, Green Publishing Associates, Inc. and John Wiley and Sons, Inc., NY at pages 6.3.1 to 6.3.6 and 2.10.3).
Two amino acid sequences are "homologous" if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximising matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively and preferably, two protein sequences (or polypeptide sequences derived from them of at least about 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater. See Dayhoff, M.O., in Atlas of Protein Sequence and Structure, pp. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Supplement 2 to this volume, pp. 1-10. The two sequences or parts thereof are more preferably homologous if their amino acids are greater than or equal to 50% identical when optimally aligned using the ALIGN program. It should be appreciated that there can be differing regions of homology within two orthologous sequences. For example, the functional sites of mouse and human orthologues may have a higher degree of homology than non-functional regions.
The term "corresponds to" is used herein to mean that a polynucleotide sequence is homologous (i.e., is identical, not strictly evolutionarily related) to all or a portion of a reference polynucleotide sequence, or that a polypeptide sequence is identical to a reference polypeptide sequence.
In contradistinction, the term "complementary to" is used herein to mean that the complementary sequence is homologous to all or a portion of a reference polynucleotide sequence. For illustration, the nucleotide sequence "TATAC" corresponds to a reference sequence "TATAC" and is complementary to a reference sequence "GTATA".
The term "sequence identity" means that two polynucleotide or amino acid sequences are identical (i.e., on a nucleotide-by-nucleotide or residue-by-residue basis) over the comparison window. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The terms "substantial identity" as used herein denotes a characteristic of a polynucleotide or amino acid sequence, wherein the polynucleotide or amino acid comprises a sequence that has at least 85 percent sequence identity, preferably at least 90 to 95 percent sequence identity, more preferably at least 99 percent sequence identity, as compared to a reference sequence over a comparison window of at least 18 nucleotide (6 amino acid) positions, frequently over a window of at least 24-48 nucleotide (8-16 amino acid) positions, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the comparison window. The reference sequence may be a subset of a larger sequence .As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Immunology - A Synthesis (2nd Edition, E.S. Golub and D.R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α-, α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include: 4- hydroxyproline, γ-carboxyglutamate, ε-Ν,Ν,Ν-trimethyllysine, ε-Ν-acetyllysine, O- phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, σ-Ν- methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention. Similarly, unless specified otherwise, the left-hand end of single-stranded polynucleotide sequences is the 5 ' end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5' direction. The direction of 5' to 3' addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA and which are 5 ' to the 5 ' end of the RNA transcript are referred to as "upstream sequences"; sequence regions on the DNA strand having the same sequence as the RNA and which are 3' to the 3' end of the RNA transcript are referred to as "downstream sequences". As applied to polypeptides, the term "substantial identity" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity, and most preferably at least 99 percent sequence identity. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur- containing side chains is cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic-aspartic, and asparagine-glutamine. As discussed herein, minor variations in the amino acid sequences of antibodies or immunoglobulin molecules are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence maintain at least 75%, more preferably at least 80%>, 90%, 95%, and most preferably 99% sequence identity to the antibodies or immunoglobulin molecules described herein. In particular, conservative amino acid replacements are contemplated. Conservative replacements are those that take place within a family of amino acids that have related side chains. Genetically encoded amino acids are generally divided into families: (1) acidic=aspartate, glutamate; (2) basic=lysine, arginine, histidine; (3) non-polar=alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar=glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. More preferred families are: serine and threonine are an aliphatic-hydroxy family; asparagine and glutamine are an amide-containing family; alanine, valine, leucine and isoleucine are an aliphatic family; and phenylalanine, tryptophan, and tyrosine are an aromatic family. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the binding function or properties of the resulting molecule, especially if the replacement does not involve an amino acid within a framework site. Whether an amino acid change results in a functional peptide can readily be determined by assaying the specific activity of the polypeptide derivative. Assays are described in detail herein. Fragments or analogs of antibodies or immunoglobulin molecules can be readily prepared by those of ordinary skill in the art. Preferred amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases. Preferably, computerised comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. Bowie et al. Science 253: 164 (1991). Thus, the foregoing examples demonstrate that those of skill in the art can recognise sequence motifs and structural conformations that may be used to define structural and functional domains in accordance with the antibodies described herein. Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. These residues are deamidated under neutral or basic conditions. The deamidated form of these residues falls within the scope of this invention.
In general, cysteine residues in proteins are either engaged in cysteine-cysteine disulfide bonds or sterically protected from the disulfide bond formation when they are a part of folded protein region. Disulfide bond formation in proteins is a complex process, which is determined by the redox potential of the environment and specialized thiol-disulfide exchanging enzymes (Creighton, Methods Enzymol. 107, 305-329, 1984; Houee-Levin, Methods Enzymol. 353, 35- 44,2002). When a cysteine residue does not have a pair in protein structure and is not sterically protected by folding, it can form a disulfide bond with a free cysteine from solution in a process known as disulfide shuffling. In another process known as disulfide scrambling, free cysteines may also interfere with naturally occurring disulfide bonds (such as those present in antibody structures) and lead to low binding, low biological activity and/or low stability.
Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogs. Analogs can include various muteins of a sequence other than the naturally occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterises the parent sequence). Examples of art-recognised polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et at. Nature 354: 105 (1991), which are each incorporated herein by reference. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds.
The term "CDR region" or "CDR" is intended to indicate the hypervariable regions of the heavy and light chains of an antibody which confer the antigen-binding specificity to the antibody. CDRs may be defined according to the Kabat system (Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th Edition. US Department of Health and Human Services, Public Service, NIH, Washington), and later editions. An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs. The term CDR or CDRs is used here in order to indicate, according to the case, one of these regions or several, or even the whole, of these regions which contain the majority of the amino acid residues responsible for the binding by affinity of the antibody for the antigen or the epitope which it recognises.
The third CDR of the heavy chain (HCDR3) has a greater size variability (greater diversity essentially due to the mechanisms of arrangement of the genes which give rise to it). It may be as short as 2 amino acids although the longest size known is 26. CDR length may also vary according to the length that can be accommodated by the particular underlying framework. Functionally, HCDR3 plays a role in part in the determination of the specificity of the antibody (Segal et al, PNAS, 71 :4298-4302, 1974, Amit et al, Science, 233:747-753, 1986, Chothia et al, J. Mol. Biol, 196:901-917, 1987, Chothia et al, Nature, 342:877- 883, 1989, Caton et al, J. Immunol, 144: 1965-1968, 1990, Sharon et al, PNAS, 87:4814-4817, 1990, Sharon et al, J. Immunol, 144:4863-4869, 1990, Kabat et al, J. Immunol, 147: 1709-1719, 1991).
The term a "set of CDRs" referred to herein comprises CDR1, CDR2 and CDR3. Thus, a set of HCDRs refers to HCDR1, HCDR2 and HCDR3, and a set of LCDRs refers to LCDR1, LCDR2 and LCDR3.
Variants of the VH and VL domains and CDRs of the present invention, including those for which amino acid sequences are set out herein, and which can be employed in targeting binding agents and antibodies for B7-H1 can be obtained by means of methods of sequence alteration or mutation and screening for antigen targeting with desired characteristics. Examples of desired characteristics include but are not limited to: increased binding affinity for antigen relative to known antibodies which are specific for the antigen; increased neutralisation of an antigen activity relative to known antibodies which are specific for the antigen if the activity is known; specified competitive ability with a known antibody or ligand to the antigen at a specific molar ratio; ability to immunoprecipitate ligand-receptor complex; ability to bind to a specified epitope; linear epitope, e.g. peptide sequence identified using peptide-binding scan, e.g. using peptides screened in linear and/or constrained conformation; conformational epitope, formed by non-continuous residues; ability to modulate a new biological activity of B7-H1, or downstream molecule; ability to bind and/or neutralise B7-H1 and/or for any other desired property. The techniques required to make substitutions within amino acid sequences of CDRs, antibody VH or VL domains and antigen binding sites are available in the art. Variants of antibody molecules disclosed herein may be produced and used in the present invention. Following the lead of computational chemistry in applying multivariate data analysis techniques to the structure/property-activity relationships (Wold, et al. Multivariate data analysis in chemistry. Chemometrics -Mathematics and Statistics in Chemistry (Ed.: B. Kowalski), D. Reidel Publishing Company, Dordrecht, Holland, 1984) quantitative activity-property relationships of antibodies can be derived using well-known mathematical techniques, such as statistical regression, pattern recognition and classification (Norman et al. Applied Regression Analysis. Wiley-Interscience; 3rd edition (April 1998); Kandel, Abraham & Backer, Eric. Computer- Assisted Reasoning in Cluster Analysis. Prentice Hall PTR, (May 11, 1995); Krzanowski, Wojtek. Principles of Multivariate Analysis: A User's Perspective (Oxford Statistical Science Series, No 22 (Paper)). Oxford University Press; (December 2000); Witten, Ian H. & Frank, Eibe. Data Mining: Practical Machine Learning Tools and Techniques with Java Implementations. Morgan Kaufmann; (October 11, 1999);Denison David G. T. (Editor), Christopher C. Holmes, Bani K. Mallick, Adrian F. M. Smith. Bayesian Methods for Nonlinear Classification and Regression (Wiley Series in Probability and Statistics). John Wiley & Sons; (July 2002); Ghose, Arup K. & Viswanadhan, Vellarkad N. Combinatorial Library Design and Evaluation Principles, Software, Tools, and Applications in Drug Discovery). In some cases the properties of antibodies can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of antibody sequence, functional and three-dimensional structures and these properties can be considered singly and in combination. An antibody antigen-binding site composed of a VH domain and a VL domain is typically formed by six loops of polypeptide: three from the light chain variable domain (VL) and three from the heavy chain variable domain (VH). Analysis of antibodies of known atomic structure has elucidated relationships between the sequence and three-dimensional structure of antibody combining sites. These relationships imply that, except for the third region (loop) in VH domains, binding site loops have one of a small number of main-chain conformations: canonical structures. The canonical structure formed in a particular loop has been shown to be determined by its size and the presence of certain residues at key sites in both the loop and in framework regions.
This study of sequence-structure relationship can be used for prediction of those residues in an antibody of known sequence, but of an unknown three-dimensional structure, which are important in maintaining the three-dimensional structure of its CDR loops and hence maintain binding specificity. These predictions can be backed up by comparison of the predictions to the output from lead optimisation experiments. In a structural approach, a model can be created of the antibody molecule using any freely available or commercial package, such as WAM. A protein visualisation and analysis software package, such as Insight II (Accelrys, Inc.) or Deep View may then be used to evaluate possible substitutions at each position in the CDR. This information may then be used to make substitutions likely to have a minimal or beneficial effect on activity or confer other desirable properties.
The term "polypeptide fragment" as used herein refers to a polypeptide that has an amino- terminal and/or carboxy-terminal deletion, but where the remaining amino acid sequence is identical to the corresponding positions in the naturally occurring sequence deduced, for example, from a full-length cDNA sequence. Fragments typically are at least 5, 6, 8 or 10 amino acids long, preferably at least 14 amino acids long, more preferably at least 20 amino acids long, usually at least 50 amino acids long, and even more preferably at least 70 amino acids long. The term "analog" as used herein refers to polypeptides which are comprised of a segment of at least 25 amino acids that has substantial identity to a portion of a deduced amino acid sequence and which has at least one of the following properties: (1) specific binding to B7-H1, under suitable binding conditions, (2) ability to block appropriate B7-H1 -protein binding, or (3) ability to inhibit B7-H1 activity. Typically, polypeptide analogs comprise a conservative amino acid substitution (or addition or deletion) with respect to the naturally occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally occurring polypeptide.
Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics". Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS p.392 (1985); and Evans et al. J. Med. Chem. 30: 1229 (1987), which are incorporated herein by reference. Such compounds are often developed with the aid of computerised molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a biochemical property or pharmacological activity), such as human antibody, but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of: -CH2NH-, -CH2S~, ~CH2-CH2-, -CH=CH-(cis and trans), - COCH2-, ~CH(OH)CH2~, and -CH2SO~, by methods well known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo and Gierasch Ann. Rev. Biochem. 61 :387 (1992), incorporated herein by reference); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclise the peptide.
As used herein "antibody" and "antibodies" (immunoglobulins) may be an oligoclonal antibody, a polyclonal antibody, a monoclonal antibody (including full-length monoclonal antibodies), a camelised antibody, a chimeric antibody, a CDR-grafted antibody, a multi-specific antibody, a bi-specific antibody, a catalytic antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an anti-idiotypic antibody and antibodies that can be labeled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques. An antibody may be from any species. An antibody comprises a polypeptide or group of polypeptides that are comprised of at least one binding domain that is formed from the folding of polypeptide chains having three- dimensional binding spaces with internal surface shapes and charge distributions complementary to the features of an antigenic determinant of an antigen. An antibody typically has a tetrameric form, comprising two identical pairs of polypeptide chains, each pair having one "light" and one "heavy" chain. The variable regions of each light/heavy chain pair form an antibody binding site. Native antibodies are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Light chains are classified as either lambda chains or kappa chains based on the amino acid sequence of the light chain constant region. The variable domain of a kappa light chain may also be denoted herein as VK. The term "variable region" may also be used to describe the variable domain of a heavy chain or light chain. Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains. The variable regions of each light/heavy chain pair form an antibody binding site. Such antibodies may be derived from any mammal, including, but not limited to, humans, monkeys, pigs, horses, rabbits, dogs, cats, mice, etc.
The term "antibody" or "antibodies" includes binding fragments of the antibodies of the invention, exemplary fragments include single-chain Fvs (scFv), single-chain antibodies, single domain antibodies, domain antibodies, Fv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-stabilised variable region (dsFv), dimeric variable region (Diabody), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), intrabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass.
Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab" fragments, and a "Fc" fragment, having no antigen-binding activity but having the ability to crystallise. Digestion of antibodies with the enzyme, pepsin, results in the a F(ab')2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites. The F(ab')2 fragment has the ability to crosslink antigen.
"Fv" when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
"Fab" when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CHI domain of the heavy chain.
dAb" when used herein refers to a fragment of an antibody that is the smallest functional binding unit of a human antibodies. A "dAb" is a single domain antibody and comprises either the variable domain of an antibody heavy chain (VH domain) or the variable domain of an antibody light chain (VL domain). Each dAb contains three of the six naturally occurring CDRs (Ward et al., Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature 341, 544-546 (1989); Holt, et al., Domain antibodies: protein for therapy, Trends Biotechnol. 21, 484-49 (2003)). With molecular weights ranging from 11 to 15 kDa, they are four times smaller than a fragment antigen binding (Fab)2 and half the size of a single chain Fv (scFv) molecule.
"Camelid" when used herein refers to antibody molecules are composed of heavy-chain dimers which are devoid of light chains, but nevertheless have an extensive antigen-binding repertoire (Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R (1993) Naturally occurring antibodies devoid of light chains. Nature 363:446-448). The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (VR) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl Acad. Sci. USA, 90:6444-6448 (1993).
It has been shown that fragments of a whole antibody can perform the function of binding antigens. Examples of binding fragments are (Ward, E.S. et al., (1989) Nature 341, 544-546) the Fab fragment consisting of VL, VH, CL and CHI domains; (McCafferty et al (1990) Nature, 348, 552-554) the Fd fragment consisting of the VH and CHI domains; (Holt et al (2003) Trends in Biotechnology 21, 484-490) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward, E.S. et al, Nature 341, 544-546 (1989), McCafferty et al (1990) Nature, 348, 552-554, Holt et al (2003) Trends in Biotechnology 21, 484-490], which consists of a VH or a VL domain; (v) isolated CDR regions; (vi) F(ab')2 fragments, a bivalent fragment comprising two linked Fab fragments (vii) single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird et al, (1988) Science, 242, 423-426, , Huston et al, (1988) PNAS USA, 85, 5879-5883); (viii) bispecific single chain Fv dimers (PCT/US92/09965) and (ix) "diabodies", multivalent or multispecific fragments constructed by gene fusion (WO94/13804; Holliger, P. (1993) et al, Proc. Natl. Acad. Sci. USA 90 6444-6448,). Fv, scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains (Reiter, Y. et al, Nature Biotech, 14, 1239-1245, 1996). Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu, S. et al, (1996) Cancer Res., 56, 3055- 3061). Other examples of binding fragments are Fab', which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CHI domain, including one or more cysteines from the antibody hinge region, and Fab'-SH, which is a Fab' fragment in which the cysteine residue(s) of the constant domains bear a free thiol group.
The term "variable" refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are responsible for the binding specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed through the variable domains of antibodies. It is concentrated in segments called Complementarity Determining Regions (CDRs) both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a β-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the β-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)). The constant domains are generally not involved directly in antigen binding, but may influence antigen binding affinity and may exhibit various effector functions, such as participation of the antibody in ADCC, CDC, and/or apoptosis.
The term "hypervariable region" when used herein refers to the amino acid residues of an antibody which are associated with its binding to antigen. The hypervariable regions encompass the amino acid residues of the "complementarity determining regions" or "CDRs" (e.g., residues 24-34 (LI), 50-56 (L2) and 89-97 (L3) of the light chain variable domain and residues 31-35 (HI), 50-65 (H2) and 95-102 (H3) of the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)) and/or those residues from a "hypervariable loop" (e.g., residues 26-32 (LI ), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (HI), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain; Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987)). "Framework" or "FR" residues are those variable domain residues flanking the CDRs. FR residues are present in chimeric, humanized, human, domain antibodies, diabodies, vaccibodies, linear antibodies, and bispecific antibodies.
As used herein, "targeted binding agent", "targeted binding protein", "specific binding protein" and like terms refer to an agent, for example an antibody, or binding fragment thereof, that preferentially binds to a target site. In one embodiment, the targeted binding agent is specific for only one target site. In other embodiments, the targeted binding agent is specific for more than one target site. In one embodiment, the targeted binding agent may be a monoclonal antibody and the target site may be an epitope. A targeted binding agent may comprise at least one antigen binding domain (e.g. a CDR) of an antibody, wherein said domain is fused or contained within a heterologous protein scaffold, e.g. a non-antibody protein scaffold.
"Binding fragments" of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, dAb and single-chain antibodies. An antibody other than a "bispecific" or "bifunctional" antibody is understood to have each of its binding sites identical. An antibody substantially inhibits adhesion of a receptor to a counter-receptor when an excess of antibody reduces the quantity of receptor bound to counter-receptor by at least about 20%, 40%>, 60%> or 80%o, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
The term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and may, but not always, have specific three-dimensional structural characteristics, as well as specific charge characteristics. An antibody is said to specifically bind an antigen when the dissociation constant is≤1 μΜ, preferably≤ 100 nM and most preferably≤ 10 nM.
The term "agent" is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
"Active" or "activity" in regard to a B7-H1 polypeptide refers to a portion of aB7-Hl polypeptide that has a biological or an immunological activity of a native B7-H1 polypeptide. "Biological" when used herein refers to a biological function that results from the activity of the native B7-H1 polypeptide. A preferred B7-H1 biological activity includes, for example, B7-H1 induced cell proliferation, cell adhesion and invasion.
"Mammal" when used herein refers to any animal that is considered a mammal. Preferably, the mammal is human.
"Animal" when used herein encompasses animals considered a mammal. Preferably the animal is human.
The term "patient" includes human and veterinary subjects.
The term "mAb" refers to monoclonal antibody. "Liposome" when used herein refers to a small vesicle that may be useful for delivery of drugs that may include the B7-H1 polypeptide of the invention or antibodies to such a B7-H1 polypeptide to a mammal.
"Label" or "labeled" as used herein refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label chemiluminescent labeled or a biotinyl group. Radioisotopes or radionuclides may include 3H, 14C, 15N, 35S, 90Y, 99Tc, mIn, 1251, 131I, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase.
Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH"), alpha-D-galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes; additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein"), dansyl, umbelliferone, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, and fiuorescamine; fluorophores such as lanthanide cryptates and chelates e.g. Europium etc (Perkin Elmer and Cisbio Assays); chemoluminescent labels or chemiluminescers, such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5-bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof, saporin or a cytotoxic fragment thereof, pokeweed antiviral toxin or a cytotoxic fragment thereof and bryodin 1 or a cytotoxic fragment thereof.
The term "pharmaceutical agent or drug" as used herein refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient. Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)), (incorporated herein by reference). As used herein, "substantially pure" means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, more preferably more than about 85%, 90%, 95%), and 99%. Most preferably, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
"Antibody-dependent cell-mediated cytotoxicity" and "ADCC" refer to a cell-mediated reaction in which non-specific cytotoxic cells that express Ig Fc receptors (FcRs) (e.g. Natural Killer (NK) cells, monocytes, neutrophils, and macrophages) recognise bound antibody on a target cell and subsequently cause lysis of the target cell. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcRs expression on hematopoietic cells is summarised in Table 9 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362, or 5,821,337 can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest can be assessed in vivo, e.g. , in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1988).
"Complement dependent cytotoxicity" and "CDC" refer to the mechanism by which antibodies carry out their cell-killing function. It is initiated by the binding of Clq, a constituent of the first component of complement, to the Fc domain of Igs, IgG or IgM, which are in complex with antigen (Hughs- Jones, N.C., and B. Gardner. 1979. Mol. Immunol. 16:697). Clq is a large, structurally complex glycoprotein of -410 kDa present in human serum at a concentration of 70 μ^ηύ (Cooper, N.R. 1985. Adv. Immunol. 37: 151). Together with two serine proteases, Clr and Cls, Clq forms the complex CI, the first component of complement. At least two of the N- terminal globular heads of Clq must be bound to the Fc of Igs for CI activation, hence for initiation of the complement cascade (Cooper, N.R. 1985. Adv. Immunol. 37: 151). The term "antibody half-life" as used herein means a pharmacokinetic property of an antibody that is a measure of the mean survival time of antibody molecules following their administration. Antibody half-life can be expressed as the time required to eliminate 50 percent of a known quantity of immunoglobulin from the patient's body or a specific compartment thereof, for example, as measured in serum or plasma, i.e., circulating half-life, or in other tissues. Half-life may vary from one immunoglobulin or class of immunoglobulin to another. In general, an increase in antibody half-life results in an increase in mean residence time (MRT) in circulation for the antibody administered.
The term "isotype" refers to the classification of an antibody's heavy or light chain constant region. The constant domains of antibodies are not involved in binding to antigen, but exhibit various effector functions. Depending on the amino acid sequence of the heavy chain constant region, a given human antibody or immunoglobulin can be assigned to one of five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. Several of these classes may be further divided into subclasses (isotypes), e.g., IgGl (gamma 1), IgG2 (gamma 2), IgG3 (gamma 3), and IgG4 (gamma 4), and IgAl and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The structures and three-dimensional configurations of different classes of immunoglobulins are well- known. Of the various human immunoglobulin classes, only human IgGl, IgG2, IgG3, IgG4, and IgM are known to activate complement. Human IgGl, IgG2, IgG3, and IgG4 are known to bind Fc gamma receptors, which mediate various effector functions including ADCC. Human light chain constant regions may be classified into two major classes, kappa and lambda.
If desired, the isotype of an antibody that specifically binds B7-H1 can be switched, for example to take advantage of a biological property of a different isotype. For example, in some circumstances it can be desirable in connection with the generation of antibodies as therapeutic antibodies against B7-H1 that the antibodies be capable of fixing complement and participating in complement-dependent cytotoxicity (CDC). There are a number of isotypes of antibodies that are capable of the same, including, without limitation, the following: murine IgM, murine IgG2a, murine IgG2b, murine IgG3, human IgM, human IgA, human IgGl, and human IgG3. In other embodiments it can be desirable in connection with the generation of antibodies as therapeutic antibodies against B7-H1 that the antibodies be capable of binding Fc receptors on effector cells and participating in antibody-dependent cytotoxicity (ADCC). There are a number of isotypes of antibodies that are capable of the same, including, without limitation, the following: murine IgG2a, murine IgG2b, murine IgG3, human IgGl, and human IgG3. It will be appreciated that antibodies that are generated need not initially possess such an isotype but, rather, the antibody as generated can possess any isotype and the antibody can be isotype switched thereafter using conventional techniques that are well known in the art. Such techniques include the use of direct recombinant techniques (see e.g., U.S. Patent No. 4,816,397), cell-cell fusion techniques (see e.g., U.S. Patent Nos. 5,916,771 and 6,207,418), among others.
By way of example, the anti- B7-H1 antibodies discussed herein are fully human antibodies. If an antibody possessed desired binding to B7-H1, it could be readily isotype switched to generate a human IgM, human IgGl, or human IgG3 isotype, while still possessing the same variable region (which defines the antibody's specificity and some of its affinity). Such molecule would then be capable of fixing complement and participating in CDC and/or be capable of binding to Fc receptors on effector cells and participating in ADCC.
"Whole blood assays" use unfractionated blood as a source of natural effectors. Blood contains complement in the plasma, together with FcR-expressing cellular effectors, such as polymorphonuclear cells (PMNs) and mononuclear cells (MNCs). Thus, whole blood assays allow simultaneous evaluation of the synergy of both ADCC and CDC effector mechanisms in vitro.
A "therapeutically effective" amount as used herein is an amount that provides some improvement or benefit to the subject. Stated in another way, a "therapeutically effective" amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom. Clinical symptoms associated with the disorders that can be treated by the methods of the invention are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
Exemplary cancers in humans include a bladder tumour, breast tumour, prostate tumour, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and CNS cancer (e.g., glioma tumour), cervical cancer, choriocarcinoma, colon and rectum cancer, connective tissue cancer, cancer of the digestive system; endometrial cancer, esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g. small cell and non-small cell); lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma, neuroblastoma, oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer, retinoblastoma; rhabdomyosarcoma; rectal cancer, renal cancer, cancer of the respiratory system; sarcoma, skin cancer; stomach cancer, testicular cancer, thyroid cancer; uterine cancer, cancer of the urinary system, as well as other carcinomas and sarcomas.
Exemplary chronic infections in humans include HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV).
The term "and/or" as used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example "A and/or B" is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.
Antibody Structure
The basic antibody structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (incorporated by reference in its entirety for all purposes). The variable regions of each light/heavy chain pair form the antibody binding site.
Thus, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are the same.
The chains all exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called CDRs. The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989).
A bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann Clin. Exp. Immunol. 79: 315-321 (1990), Kostelny et al. J. Immunol. 148: 1547-1553 (1992). Bispecific antibodies do not exist in the form of fragments having a single binding site (e.g., Fab, Fab', and Fv).
Typically, a VH domain is paired with a VL domain to provide an antibody antigen- binding site, although a VH or VL domain alone may be used to bind antigen. The VH domain (see Table 9) may be paired with the VL domain (see Table 13), so that an antibody antigen- binding site is formed comprising both the VH and VL domains
Human antibodies and humanisation of antibodies
Human antibodies avoid some of the problems associated with antibodies that possess murine or rat variable and/or constant regions. The presence of such murine or rat derived proteins can lead to the rapid clearance of the antibodies or can lead to the generation of an immune response against the antibody by a patient. In order to avoid the utilisation of murine or rat derived antibodies, fully human antibodies can be generated through the introduction of functional human antibody loci into a rodent, other mammal or animal so that the rodent, other mammal or animal produces fully human antibodies.
One method for generating fully human antibodies is through the use of XenoMouse® strains of mice that have been engineered to contain up to but less than 1000 kb-sised germline configured fragments of the human heavy chain locus and kappa light chain locus. See Mendez et al. Nature Genetics 15: 146-156 (1997) and Green and Jakobovits J. Exp. Med. 188:483-495 (1998). The XenoMouse® strains are available from Amgen, Inc. (Fremont, California, U.S.A).
Such mice, then, are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilised for achieving the same are disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15:146-156 (1997), the disclosure of which is hereby incorporated by reference.
The production of the XenoMouse® strains of mice is further discussed and delineated in U.S. Patent Application Serial Nos. 07/466,008, filed January 12, 1990, 07/610,515, filed November 8, 1990, 07/919,297, filed July 24, 1992, 07/922,649, filed July 30, 1992, 08/031,801, filed March 15, 1993, 08/112,848, filed August 27, 1993, 08/234,145, filed April 28, 1994, 08/376,279, filed January 20, 1995, 08/430, 938, filed April 27, 1995, 08/464,584, filed June 5, 1995, 08/464,582, filed June 5, 1995, 08/463,191, filed June 5, 1995, 08/462,837, filed June 5, 1995, 08/486,853, filed June 5, 1995, 08/486,857, filed June 5, 1995, 08/486,859, filed June 5,
1995, 08/462,513, filed June 5, 1995, 08/724,752, filed October 2, 1996, 08/759,620, filed December 3, 1996, U.S. Publication 2003/0093820, filed November 30, 2001 and U.S. Patent Nos. 6,162,963, 6,150,584, 6,114,598, 6,075,181, and 5,939,598 and Japanese Patent Nos. 3 068 180 B2, 3 068 506 B2, and 3 068 507 B2. See also European Patent No., EP 0 463 151 Bl, grant published June 12, 1996, International Patent Application No., WO 94/02602, published February 3, 1994, International Patent Application No., WO 96/34096, published October 31,
1996, WO 98/24893, published June 11, 1998, WO 00/76310, published December 21, 2000. The disclosures of each of the above-cited patents, applications, and references are hereby incorporated by reference in their entirety.
In an alternative approach, others, including GenPharm International, Inc., have utilised a
"minilocus" approach. In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus. Thus, one or more VH genes, one or more DH genes, one or more JH genes, a mu constant region, and usually a second constant region
(preferably a gamma constant region) are formed into a construct for insertion into an animal.
This approach is described in U.S. Patent No. 5,545,807 to Surani et al. and U.S. Patent Nos.
5,545,806, 5,625,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650, 5,814,318,
5,877,397, 5,874,299, and 6,255,458 each to Lonberg and Kay, U.S. Patent No. 5,591,669 and 6,023.010 to Krimpenfort and Berns, U.S. Patent Nos. 5,612,205, 5,721,367, and 5,789,215 to
Berns et al., and U.S. Patent No. 5,643,763 to Choi and Dunn, and GenPharm International U.S. Patent Application Serial Nos. 07/574,748, filed August 29, 1990, 07/575,962, filed August 31, 1990, 07/810,279, filed December 17, 1991, 07/853,408, filed March 18, 1992, 07/904,068, filed June 23, 1992, 07/990,860, filed December 16, 1992, 08/053,131, filed April 26, 1993, 08/096,762, filed July 22, 1993, 08/155,301, filed November 18, 1993, 08/161,739, filed December 3, 1993, 08/165,699, filed December 10, 1993, 08/209,741, filed March 9, 1994, the disclosures of which are hereby incorporated by reference. See also European Patent No. 0 546 073 Bl, International Patent Application Nos. WO 92/03918, WO 92/22645, WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO 96/14436, WO 97/13852, and WO 98/24884 and U.S. Patent No. 5,981,175, the disclosures of which are hereby incorporated by reference in their entirety. See further Taylor et al, 1992, Chen et al, 1993, Tuaillon et al, 1993, Choi et al, 1993, Lonberg et al, (1994), Taylor et al, (1994), and Tuaillon et al, (1995), Fishwild et al, (1996), the disclosures of which are hereby incorporated by reference in their entirety.
Kirin has also demonstrated the generation of human antibodies from mice in which, through microcell fusion, large pieces of chromosomes, or entire chromosomes, have been introduced. See European Patent Application Nos. 773 288 and 843 961, the disclosures of which are hereby incorporated by reference. Additionally, KM™- mice, which are the result of cross-breeding of Kirin's Tc mice with Medarex's minilocus (Humab) mice have been generated. These mice possess the human IgH transchromosome of the Kirin mice and the kappa chain transgene of the Genpharm mice (Ishida et al, Cloning Stem Cells, (2002) 4:91-102).
Human antibodies can also be derived by in vitro methods. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display, and the like. Preparation of Antibodies
Antibodies, as described herein, were prepared through the utilization of the XenoMouse® technology, as described below. Such mice are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilised for achieving the same are disclosed in the patents, applications, and references disclosed in the background section herein. In particular, however, a preferred embodiment of transgenic production of mice and antibodies therefrom is disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15: 146-156 (1997), the disclosure of which is hereby incorporated by reference.
Through the use of such technology, fully human monoclonal antibodies to a variety of antigens have been produced. Essentially, XenoMouse® lines of mice are immunised with an antigen of interest (e.g. B7-H1), lymphatic cells (such as B-cells) are recovered from the hyper- immunised mice, and the recovered lymphocytes are fused with a myeloid-type cell line to prepare immortal hybridoma cell lines. These hybridoma cell lines are screened and selected to identify hybridoma cell lines that produced antibodies specific to the antigen of interest. Provided herein are methods for the production of multiple hybridoma cell lines that produce antibodies specific to B7-H1. Further, provided herein are characterisation of the antibodies produced by such cell lines, including nucleotide and amino acid sequence analyses of the heavy and light chains of such antibodies.
Alternatively, instead of being fused to myeloma cells to generate hybridomas, B cells can be directly assayed. For example, CD 19+ B cells can be isolated from hyperimmune XenoMouse® mice and allowed to proliferate and differentiate into antibody-secreting plasma cells. Antibodies from the cell supernatants are then screened by ELISA for reactivity against the B7-H1 immunogen. The supernatants might also be screened for immunoreactivity against fragments of B7-H1 to further map the different antibodies for binding to domains of functional interest on B7-H1. The antibodies may also be screened other related human proteins and against the rat, the mouse, and non-human primate, such as Cynomolgus monkey, orthologues of B7-H1, the last to determine species cross-reactivity. B cells from wells containing antibodies of interest may be immortalised by various methods including fusion to make hybridomas either from individual or from pooled wells, or by infection with EBV or transfection by known immortalising genes and then plating in suitable medium. Alternatively, single plasma cells secreting antibodies with the desired specificities are then isolated using a B7-H1 -specific hemolytic plaque assay (see for example Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48 (1996)). Cells targeted for lysis are preferably sheep red blood cells (SRBCs) coated with the B7-H1 antigen. In the presence of a B-cell culture containing plasma cells secreting the immunoglobulin of interest and complement, the formation of a plaque indicates specific B7-H1 -mediated lysis of the sheep red blood cells surrounding the plasma cell of interest. The single antigen-specific plasma cell in the center of the plaque can be isolated and the genetic information that encodes the specificity of the antibody is isolated from the single plasma cell. Using reverse-transcription followed by PCR (RT-PCR), the DNA encoding the heavy and light chain variable regions of the antibody can be cloned. Such cloned DNA can then be further inserted into a suitable expression vector, preferably a vector cassette such as a pcDNA, more preferably such a pcDNA vector containing the constant domains of immunglobulin heavy and light chain. The generated vector can then be transfected into host cells, e.g., HEK293 cells, CHO cells, and cultured in conventional nutrient media modified as appropriate for inducing transcription, selecting transformants, or amplifying the genes encoding the desired sequences.
As will be appreciated, antibodies as described herein can be expressed in cell lines other than hybridoma cell lines. Sequences encoding particular antibodies can be used to transform a suitable mammalian host cell. Transformation can be by any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus (or into a viral vector) and transducing a host cell with the virus (or vector) or by transfection procedures known in the art, as exemplified by U.S. Patent Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents are hereby incorporated herein by reference). The transformation procedure used depends upon the host to be transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.
Mammalian cell lines available as hosts for expression are well known in the art and include many immortalised cell lines available from the NCIMB, including but not limited to Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), human epithelial kidney 293 cells (Hek293), and a number of other cell lines. Cell lines of particular preference are selected through determining which cell lines have high expression levels and produce antibodies with constitutive B7-H1 binding properties. In the cell-cell fusion technique, a myeloma, CHO cell or other cell line is prepared that possesses a heavy chain with any desired isotype and another myeloma, CHO cell or other cell line is prepared that possesses the light chain. Such cells can, thereafter, be fused and a cell line expressing an intact antibody can be isolated.
Accordingly, as antibody candidates are generated that meet desired "structural" attributes as discussed above, they can generally be provided with at least certain of the desired "functional" attributes through isotype switching.
In the cell-cell fusion technique, a myeloma, CHO cell or other cell line is prepared that possesses a heavy chain with any desired isotype and another myeloma, CHO cell or other cell line is prepared that possesses the light chain. Such cells can, thereafter, be fused and a cell line expressing an intact antibody can be isolated.
Accordingly, as antibody candidates are generated that meet desired "structural" attributes as discussed above, they can generally be provided with at least certain of the desired "functional" attributes through isotype switching.
Antibody Sequences
Embodiments of the invention include the antibodies listed below in Table 1. This table reports the identification number of each antibody, along with the SEQ ID number of the variable domain of the corresponding heavy chain and light chain genes and polypeptides, respectively. Each antibody sequence has been given an identification number.
Table 1
Figure imgf000071_0001
Nucleotide sequence encoding the variable region of the light chain 16
Amino acid sequence encoding the variable region of the light chain 17
Nucleotide sequence encoding the variable region of the heavy chain 21
Amino acid sequence encoding the variable region of the heavy chain 22
2.14H9
Nucleotide sequence encoding the variable region of the light chain 26
Amino acid sequence encoding the variable region of the light chain 27
Nucleotide sequence encoding the variable region of the heavy chain 31
Amino acid sequence encoding the variable region of the heavy chain 32
2.20A8
Nucleotide sequence encoding the variable region of the light chain 36
Amino acid sequence encoding the variable region of the light chain 37
Nucleotide sequence encoding the variable region of the heavy chain 41
Amino acid sequence encoding the variable region of the heavy chain 42
3.15G8
Nucleotide sequence encoding the variable region of the light chain 46
Amino acid sequence encoding the variable region of the light chain 47
Nucleotide sequence encoding the variable region of the heavy chain 51
Amino acid sequence encoding the variable region of the heavy chain 52
3.18G1
Nucleotide sequence encoding the variable region of the light chain 56
Amino acid sequence encoding the variable region of the light chain 57
Nucleotide sequence encoding the variable region of the heavy chain 61
2.7A4 Amino acid sequence encoding the variable region of the heavy chain 62
OPT Nucleotide sequence encoding the variable region of the light chain 66
Amino acid sequence encoding the variable region of the light chain 67
Nucleotide sequence encoding the variable region of the heavy chain 71
2.14H9 Amino acid sequence encoding the variable region of the heavy chain 72
OPT Nucleotide sequence encoding the variable region of the light chain 76
Amino acid sequence encoding the variable region of the light chain 77
Therapeutic Administration and Formulations
Embodiments of the invention include sterile pharmaceutical formulations of anti-B7-Hl antibodies that are useful as treatments for diseases. Such formulations would inhibit the binding of B7-H1 to one or more of its cognate ligands, thereby treating pathological conditions where, for example, serum or tissue B7-H1 is abnormally elevated. Antibodies of the invention preferably possess adequate affinity to potently inhibit B7-H1 activity, or inhibit B7-H1 binding to one or more of its cognate ligands, and preferably have an adequate duration of action to allow for infrequent dosing in humans. A prolonged duration of action will allow for less frequent and more convenient dosing schedules by alternate parenteral routes such as subcutaneous or intramuscular injection.
Sterile formulations can be created, for example, by filtration through sterile filtration membranes, prior to or following lyophilisation and reconstitution of the antibody. The antibody ordinarily will be stored in lyophilised form or in solution. Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having an adapter that allows retrieval of the formulation, such as a stopper pierceable by a hypodermic injection needle.
The route of antibody administration is in accord with known methods, e.g., injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intrathecal, inhalation or intralesional routes, direct injection to a tumour site, or by sustained release systems as noted below. The antibody is preferably administered continuously by infusion or by bolus injection.
An effective amount of antibody to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred that the therapist titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Typically, the clinician will administer antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or by the assays described herein.
Antibodies, as described herein, can be prepared in a mixture with a pharmaceutically acceptable carrier. This therapeutic composition can be administered intravenously or through the nose or lung, preferably as a liquid or powder aerosol (lyophilised). The composition can also be administered parenterally or subcutaneously as desired. When administered systemically, the therapeutic composition should be sterile, pyrogen-free and in a parenterally acceptable solution having due regard for pH, isotonicity, and stability. These conditions are known to those skilled in the art. Briefly, dosage formulations of the compounds described herein are prepared for storage or administration by mixing the compound having the desired degree of purity with pharmaceutically acceptable carriers, excipients, or stabilisers. Such materials are non-toxic to the recipients at the dosages and concentrations employed, and include buffers such as TRIS HC1, phosphate, citrate, acetate and other organic acid salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium and/or nonionic surfactants such as TWEEN, PLURONICS or poly ethylenegly col.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (20th ed, Lippincott Williams & Wilkens Publishers (2003)). For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the polypeptide, which matrices are in the form of shaped articles, films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) as described by Langer et al, J. Biomed Mater. Res., (1981) 15: 167-277 and Langer, Chem. Tech., (1982) 12:98-105, or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al, Biopolymers, (1983) 22:547-556), non- degradable ethylene -vinyl acetate (Langer et al, supra), degradable lactic acid-glycolic acid copolymers such as the LUPRON Depot™ (injectable microspheres composed of lactic acid- glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid (EP 133,988).
While polymers such as ethylene -vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated proteins remain in the body for a long time, they can denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for protein stabilisation depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through disulfide interchange, stabilisation can be achieved by modifying sulfhydryl residues, lyophilising from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
Sustained-released compositions also include preparations of crystals of the antibody suspended in suitable formulations capable of maintaining crystals in suspension. These preparations when injected subcutaneous ly or intraperitonealy can produce a sustained release effect. Other compositions also include liposomally entrapped antibodies. Liposomes containing such antibodies are prepared by methods known per se: U.S. Pat. No. DE 3,218,121; Epstein et al, Proc. Natl. Acad. Sci. USA, (1985) 82:3688-3692; Hwang et al, Proc. Natl. Acad. Sci. USA, (1980) 77:4030-4034; EP 52,322; EP 36,676; EP 88,046; EP 143,949; 142,641; Japanese patent application 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324.
The dosage of the antibody formulation for a given patient will be determined by the attending physician taking into consideration various factors known to modify the action of drugs including severity and type of disease, body weight, sex, diet, time and route of administration, other medications and other relevant clinical factors. Therapeutically effective dosages can be determined by either in vitro or in vivo methods.
An effective amount of the antibodies, described herein, to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. A typical daily dosage might range from about 0.000 lmg/kg, O.OOlmg/kg, O.Olmg/kg, O.lmg/kg, lmg/kg, lOmg/kg to up to lOOmg/kg, lOOOmg/kg, lOOOOmg/kg or more, of the patient's body weight depending on the factors mentioned above. The dosage may be between 0.0001 mg/kg and 20 mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5 mg/kg, 0.0001 and 2 mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and 0.75 mg/kg, 0.0001 mg/kg and 0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg, 0.0001 to 0.15 mg/kg, 0.0001 to 0.10 mg/kg, 0.001 to 0.5 mg/kg, 0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kg of the patient's body weight depending on the factors mentioned above. Typically, the clinician will administer the therapeutic antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or as described herein.
Doses of antibodies of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
It will be appreciated that administration of therapeutic entities in accordance with the compositions and methods herein will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures can be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. "Pharmaceutical excipient development: the need for preclinical guidance." Regul. Toxicol. Pharmacol. 32(2) :210-8 (2000), Wang W. "Lyophilisation and development of solid protein pharmaceuticals." Int. J. Pharm. 203(1-2): 1-60 (2000), Charman WN "Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts." J Pharm Sci .89(8):967-78 (2000), Powell et al. "Compendium of excipients for parenteral formulations" PDA J Pharm Sci Technol. 52:238-311 (1998) and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.
Design and Generation of Other Therapeutics
In accordance with the present invention and based on the activity of the antibodies that are produced and characterised herein with respect to B7-H1, the design of other therapeutic modalities beyond antibody moieties is facilitated and disclosed to one skilled in the art. Such modalities include, without limitation, advanced antibody therapeutics, such as bispecific antibodies, immunotoxins, radiolabeled therapeutics, and single antibody V domains, antibodylike binding agent based on other than V region scaffolds, single domain antibodies, generation of peptide therapeutics, B7-H1 binding domains in novel scaffolds, gene therapies, particularly intrabodies, antisense therapeutics, and small molecules.
An antigen binding site may be provided by means of arrangement of CDRs on non- antibody protein scaffolds, such as fibronectin or cytochrome B etc. (Haan & Maggos (2004) BioCentury, 12(5): A1-A6; Koide et al. (1998) Journal of Molecular Biology, 284: 1141-1151; Nygren et al. (1997) Current Opinion in Structural Biology, 7: 463-469) or by randomising or mutating amino acid residues of a loop within a protein scaffold to confer binding specificity for a desired target. Scaffolds for engineering novel binding sites in proteins have been reviewed in detail by Nygren et al. (Nygren et al. (1997) Current Opinion in Structural Biology, 7: 463-469). Protein scaffolds for antibody mimics are disclosed in WO/0034784, which is herein incorporated by reference in its entirety, in which the inventors describe proteins (antibody mimics) that include a fibronectin type III domain having at least one randomised loop. A suitable scaffold into which to graft one or more CDRs, e.g. a set of HCDRs, may be provided by any domain member of the immunoglobulin gene superfamily. The scaffold may be a human or non-human protein. An advantage of a non-antibody protein scaffold is that it may provide an antigen-binding site in a scaffold molecule that is smaller and/or easier to manufacture than at least some antibody molecules. Small size of a binding member may confer useful physiological properties, such as an ability to enter cells, penetrate deep into tissues or reach targets within other structures, or to bind within protein cavities of the target antigen. Use of antigen binding sites in non-antibody protein scaffolds is reviewed in Wess, 2004 (Wess, L. In: BioCentury, The Bernstein Report on BioBusiness, 12(42), A1-A7, 2004). Typical are proteins having a stable backbone and one or more variable loops, in which the amino acid sequence of the loop or loops is specifically or randomly mutated to create an antigen-binding site that binds the target antigen. Such proteins include the IgG-binding domains of protein A from S. aureus, transferrin, albumin, tetranectin, fibronectin (e.g. 10th fibronectin type III domain), lipocalins as well as gamma- crystalline and other Affilin™ scaffolds (Scil Proteins). Examples of other approaches include synthetic "Microbodies" based on cyclotides - small proteins having intra-molecular disulphide bonds, Microproteins (Versabodies™, Amunix) and ankyrin repeat proteins (DARPins, Molecular Partners). In addition to antibody sequences and/or an antigen-binding site, a targeted binding agent according to the present invention may comprise other amino acids, e.g. forming a peptide or polypeptide, such as a folded domain, or to impart to the molecule another functional characteristic in addition to ability to bind antigen. Targeted binding agents of the invention may carry a detectable label, or may be conjugated to a toxin or a targeting moiety or enzyme (e.g. via a peptidyl bond or linker). For example, a targeted binding agent may comprise a catalytic site (e.g. in an enzyme domain) as well as an antigen binding site, wherein the antigen binding site binds to the antigen and thus targets the catalytic site to the antigen. The catalytic site may inhibit biological function of the antigen, e.g. by cleavage.
In connection with the generation of advanced antibody therapeutics, where complement fixation is a desirable attribute, it can be possible to sidestep the dependence on complement for cell killing through the use of bispecific antibodies, immunotoxins, or radiolabels, for example.
For example, bispecific antibodies can be generated that comprise (i) two antibodies one with a specificity to B7-H1 and another to a second molecule that are conjugated together, (ii) a single antibody that has one chain specific to B7-H1 and a second chain specific to a second molecule, or (iii) a single chain antibody that has specificity to B7-H1 and the other molecule. Such bispecific antibodies can be generated using techniques that are well known; for example, in connection with (i) and (ii) see e.g., Fanger et al. Immunol Methods 4:72-81 (1994) and Wright and Harris, supra, and in connection with (iii) see e.g., Traunecker et al. Int. J. Cancer (Suppl.) 7:51-52 (1992). In each case, the second specificity can be made as desired. For example, the second specificity can be made to the heavy chain activation receptors, including, without limitation, CD 16 or CD64 {see e.g., Deo et al. Immunol. Today 18:127 (1997)) or CD89 {see e.g., Valerius et al. Blood 90:4485-4492 (1997)).
Antibodies can also be modified to act as immunotoxins utilising techniques that are well known in the art. See e.g., Vitetta Immunol Today 14:252 (1993). See also U.S. Patent No. 5,194,594. In connection with the preparation of radiolabeled antibodies, such modified antibodies can also be readily prepared utilising techniques that are well known in the art. See e.g., Junghans et al. in Cancer Chemotherapy and Biotherapy 655-686 (2d edition, Chafner and Longo, eds., Lippincott Raven (1996)). See also U.S. Patent Nos. 4,681,581, 4,735,210, 5,101,827, 5,102,990 (RE 35,500), 5,648,471, and 5,697,902. Each immunotoxin or radiolabeled molecule would be likely to kill cells expressing the desired multimeric enzyme subunit oligomerisation domain.
When an antibody is linked to an agent (e.g., radioisotope, pharmaceutical composition, or a toxin) it is contemplated that the agent possesses a pharmaceutical property selected from the group of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents and combinations thereof. The agent can be selected from the group of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antimetabolites, antibiotics, enzymes, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, antagonists, endostatin, taxols, camptothecins, oxaliplatin, doxorubicins and their analogs, and a combination thereof. Examples of toxins further include gelonin, Pseudomonas exotoxin (PE), PE40, PE38, diphtheria toxin, ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, Pseudomonas endotoxin, members of the enediyne family of molecules, such as calicheamicin and esperamicin, as well as derivatives, combinations and modifications thereof. Chemical toxins can also be taken from the group consisting of duocarmycin (see, e.g., U.S. Patent No. 5,703,080 and U.S. Patent No. 4,923,990), methotrexate, doxorubicin, melphalan, chlorambucil, ARA-C, vindesine, mitomycin C, cis-platinum, etoposide, bleomycin and 5-fluorouracil. Examples of chemotherapeutic agents also include Adriamycin, Doxorubicin, 5-Fluorouracil, Cytosine arabinoside (Ara-C), Cyclophosphamide, Thiotepa, Taxotere (docetaxel), Busulfan, Cytoxin, Taxol, Methotrexate, Cisplatin, Melphalan, Vinblastine, Bleomycin, Etoposide, Ifosfamide, Mitomycin C, Mitoxantrone, Vincreistine, Vinorelbine, Carboplatin, Teniposide, Daunomycin, Carminomycin, Aminopterin, Dactinomycin, Mitomycins, Esperamicins (see, U.S. Patent No. 4,675,187), Melphalan, and other related nitrogen mustards. Suitable toxins and chemotherapeutic agents are described in Remington's Pharmaceutical Sciences, 19th Ed. (Mack Publishing Co. 1995), and in Goodman And Gilman's The Pharmacological Basis of Therapeutics, 7th Ed. (MacMillan Publishing Co. 1985). Other suitable toxins and/or chemotherapeutic agents are known to those of skill in the art.
Examples of radioisotopes include gamma-emitters, positron-emitters, and x-ray emitters that can be used for localisation and/or therapy, and beta-emitters and alpha-emitters that can be used for therapy. The radioisotopes described previously as useful for diagnostics, prognostics and staging are also useful for therapeutics.
Non-limiting examples of anti-cancer or anti-leukemia agents include anthracyclines such as doxorubicin (adriamycin), daunorubicin (daunomycin), idarubicin, detorubicin, carminomycin, epirubicin, esorubicin, and morpholino and substituted derivatives, combinations and modifications thereof. Exemplary pharmaceutical agents include cis-platinum, taxol, calicheamicin, vincristine, cytarabine (Ara-C), cyclophosphamide, prednisone, daunorubicin, idarubicin, fludarabine, chlorambucil, interferon alpha, hydroxyurea, temozolomide, thalidomide, and bleomycin, and derivatives, combinations and modifications thereof. Preferably, the anti- cancer or anti-leukemia is doxorubicin, morpholinodoxorubicin, or morpholinodaunorubicin.
The antibodies of the invention also encompass antibodies that have half-lives (e.g., serum half-lives) in a mammal, preferably a human, of greater than that of an unmodified antibody. In one embodiment, said antibody half life is greater than about 15 days, greater than about 20 days, greater than about 25 days, greater than about 30 days, greater than about 35 days, greater than about 40 days, greater than about 45 days, greater than about 2 months, greater than about 3 months, greater than about 4 months, or greater than about 5 months. The increased half- lives of the antibodies of the present invention or fragments thereof in a mammal, preferably a human, result in a higher serum titer of said antibodies or antibody fragments in the mammal, and thus, reduce the frequency of the administration of said antibodies or antibody fragments and/or reduces the concentration of said antibodies or antibody fragments to be administered. Antibodies or fragments thereof having increased in vivo half-lives can be generated by techniques known to those of skill in the art. For example, antibodies or fragments thereof with increased in vivo half-lives can be generated by modifying (e.g., substituting, deleting or adding) amino acid residues identified as involved in the interaction between the Fc domain and the FcRn receptor (see, e.g., International Publication Nos. WO 97/34631 and WO 02/060919, which are incorporated herein by reference in their entireties). Antibodies or fragments thereof with increased in vivo half-lives can be generated by attaching to said antibodies or antibody fragments polymer molecules such as high molecular weight polyethyleneglycol (PEG). PEG can be attached to said antibodies or antibody fragments with or without a multifunctional linker either through site-specific conjugation of the PEG to the N- or C-terminus of said antibodies or antibody fragments or via epsilon-amino groups present on lysine residues. Linear or branched polymer derivatisation that results in minimal loss of biological activity will be used. The degree of conjugation will be closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of PEG molecules to the antibodies. Unreacted PEG can be separated from antibody- PEG conjugates by, e.g., size exclusion or ion-exchange chromatography.
As will be appreciated by one of skill in the art, in the above embodiments, while affinity values can be important, other factors can be as important or more so, depending upon the particular function of the antibody. For example, for an immunotoxin (toxin associated with an antibody), the act of binding of the antibody to the target can be useful; however, in some embodiments, it is the internalisation of the toxin into the cell that is the desired end result. As such, antibodies with a high percent internalisation can be desirable in these situations. Thus, in one embodiment, antibodies with a high efficiency in internalisation are contemplated. A high efficiency of internalisation can be measured as a percent internalised antibody, and can be from a low value to 100%. For example, in varying embodiments, 0.1-5, 5-10, 10-20, 20-30, 30-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-99, and 99-100% can be a high efficiency. As will be appreciated by one of skill in the art, the desirable efficiency can be different in different embodiments, depending upon, for example, the associated agent, the amount of antibody that can be administered to an area, the side effects of the antibody-agent complex, the type (e.g., cancer type) and severity of the problem to be treated.
In other embodiments, the antibodies disclosed herein provide an assay kit for the detection of B7-H1 expression in mammalian tissues or cells in order to screen for a disease or disorder associated with changes in expression of B7-H1. The kit comprises an antibody that binds B7-H1 and means for indicating the reaction of the antibody with the antigen, if present.
In some embodiments, an article of manufacture is provided comprising a container, comprising a composition containing an antibody that specifically binds B7-H1 , and a package insert or label indicating that the composition can be used to treat disease mediated by B7-H1 expression. Preferably a mammal and, more preferably, a human, receives the antibody that specifically binds B7-H1.
Combinations
The anti-tumour treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery, bone marrow and peripheral stem cell transplantations or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti tumour agents:
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6- methylphenyl)-2- {6-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or inhibitors of cathepsin activity, inhibitors of serine proteases for example matriptase, hepsin, urokinase and inhibitors of integrin ανβ6 function.
(iv) cytotoxic agents such as fludarabine, 2-chlorodeoxyadenosine, chlorambucil or doxorubicin and combination thereoff such as Fludarabine + cyclophosphamide, CVP: cyclophosphamide + vincristine + prednisone, ACVBP: doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone, CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone, CNOP: cyclophosphamide + mitoxantrone + vincristine + prednisone, m-BACOD: methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone + leucovorin., MACOP-B: methotrexate + doxorubicin + cyclophosphamide + vincristine + prednisone fixed dose + bleomycin + leucovorin, or ProMACE CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + methotrexate + leucovorin.
(v) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3 -chloro-4-fluorophenyl)-7-(3 -morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors, and inhibitors of survival signaling proteins such as Bcl-2, Bcl-XL for example ABT-737;
(vi) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™)] and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2- fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856, WO 98/13354, WOOO/47212 and WOO 1/32651, anti-vascular endothelial growth factor receptor antibodies such anti-KDR antibodies and anti-fit 1 antibodies,) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ανβ3 function and angiostatin)] or colony stimulating factor 1 (CSF1) or CSF1 receptor; Additional details on AZD2171 may be found in Wedge et al (2005) Cancer Research. 65(10):4389-400. Additional details on AZD6474 may be found in Ryan & Wedge (2005) British Journal of Cancer. 92 Suppl 1 :S6-13. Both publications are herein incorporated by reference in their entireties.
(vii) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense or G3139 (Genasense), an anti bcl2 antisense;
(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
(x) immunotherapy approaches, including for example treatment with Alemtuzumab (campath-lH™), a monoclonal antibody directed at CD52, or treatment with antibodies directed at CD22, ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy such as treatment with monoclonal antibodies inhibiting CTLA-4 function, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies, adoptive T-cell transfer using T-cells that have been non-specifically activated or targeted to a specific antigen of interest ex vivo;
(xi) Vaccination approaches, including for example treatment with a vaccine directed against a specific viral infection such as HIV or HBV, or treatment with a vaccine directed against a specific tumour antigen; (xii) inhibitors of protein degradation such as proteasome inhibitor such as Velcade (bortezomid); and
(xiii) biotherapeutic therapeutic approaches for example those which use peptides or proteins (such as antibodies or soluble external receptor domain constructions) which either sequester receptor ligands, block ligand binding to receptor or decrease receptor signalling (e.g. due to enhanced receptor degradation or lowered expression levels).
In one embodiment the anti-tumour treatment defined herein may involve, in addition to the compounds of the invention, treatment with other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxalip latin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin).
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range. EXAMPLES
The following examples, including the experiments conducted and results achieved are provided for illustrative purposes only and are not to be construed as limiting upon the teachings herein. EXAMPLE 1: EXPRESSION OF RECOMBINANT HUMAN B7-H1
The human B7-H1 cDNA (Dong, H. et al, 1999, Nat. Med. 5: 1365 - 1369) was amplified from Image clone 7262208 (ATCC) using polymerase chain reaction (PCR) and then cloned into the Nhe 1 and EcoRl sites of pcr3.1Bid vector. This construct was lipofected into CHO cells (American Type Tissue Collection, catalog # CCL-61) and the expression on the cell surface was confirmed by fluorescent activated cell sorting (FACS) analysis.
The extracellular domain of human B7-H1 (amino acid residues 1-239) fused to the Fc region of human IgGl was purchased from R&D Systems Inc., catalog # 156-B7-100. EXAMPLE 2: IMMUNISATION AND TITERING
Immunisation
Monoclonal antibodies against human B7-H1 were developed by sequentially immunizing XenoMouse® mice (XenoMouse strains: XMG2 (IgG2 kappa/lambda) and XMG4 (IgG4 kappa/lambda) Amgen, Inc. Vancouver, British Columbia, Canada) with either 5-10 ug of the B7-Hl/Fc chimera protein or 1-2x10(6) CHO cells expressing recombinant human B7-H1 as described in Example 1.
Immunisations were conducted according to the methods disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. The immunisation programs are summarised in Table 2.
Selection of Animals for Harvest by Titer
Titres of antibodies in sera from the immunised mice were determined in an ELISA assay. Plates (Corning Costar, cat# 3368) were coated with the human B7-Hl/Fc protein (R&D Systems Inc., catalog # 156-B7-100). B7-H1 -specific antibodies were detected with mouse anti-human IgG antibody and goat anti-mouse IgG Fc antibody conjugated to horseradish peroxidase. Typically, five animals with the highest titres within each immunization cohort were selected for lymphocyte isolation and generation of hybridomas. Table 2. Summary of Immunisation Programs
Group Immunogen Strain No of Immunisation
mice routes
Recombinant human B7 IgG2 IP/SC, twice/wk, for
Hl/Fc protein 5 weeks
Recombinant human B7 IgG4 IP/SC, twice/wk, for
Hl/Fc protein 5 weeks
CHO cells expressing IgG2 IP/SC, twice/wk, for human B7-H1 5 weeks
CHO cells expressing IgG4 IP/SC, twice/wk, for human B7-H1 5 weeks
ΊΡ" refers to "intraperitoneal" and "SC" refers to "subcutaneous'
EXAMPLE 3: RECOVERY OF LYMPHOCYTES, B-CELL ISOLATIONS, FUSIONS
AND GENERATION OF HYBRIDOMAS
Immunised mice were sacrificed by cervical dislocation, and the draining lymph nodes harvested and pooled from each cohort. The lymphoid cells were dissociated by grinding in DMEM to release the cells from the tissues and the cells were suspended in DMEM. The cells were counted, and 0.9 ml DMEM per 100 million lymphocytes added to the cell pellet to resuspend the cells gently but completely. Using 100 μΐ of CD90+ magnetic beads per 100 million cells, the cells were labeled by incubating the cells with the magnetic beads at 4°C for 15 minutes. The magnetically labeled cell suspension containing up to 108 positive cells (or up to 2xl09 total cells) was loaded onto a LS+ column and the column washed with DMEM. The total effluent was collected as the CD90-negative fraction (most of these cells were expected to be B cells).
The fusion was performed by mixing washed enriched B cells from above and nonsecretory myeloma P3X63Ag8.653 cells purchased from ATCC, cat.# CRL 1580 (Kearney et al, J. Immunol. 123, 1979, 1548-1550) at a ratio of 1 :1. The cell mixture was gently pelleted by centrifugation at 800 x g. After complete removal of the supernatant, the cells were treated with 2-4 mL of Pronase solution (CalBiochem, cat. # 53702; 0.5 mg/ml in PBS) for no more than 2 minutes. Then 3-5 ml of FBS was added to stop the enzyme activity and the suspension was adjusted to 40 ml total volume using electro cell fusion solution, (ECFS, 0.3M Sucrose, Sigma, Cat# S7903, 0.1 mM Magnesium Acetate, Sigma, Cat# M2545, 0.1 mM Calcium Acetate, Sigma, Cat# C4705). The supernatant was removed after centrifugation and the cells were resuspended in 40 ml ECFS. This wash step was repeated and the cells again were resuspended in ECFS to a concentration of 2x106 cells/ml.
Electro-cell fusion was performed using a fusion generator (model ECM2001, Genetronic, Inc., San Diego, CA). The fusion chamber size used was 2.0 ml, using the following instrument settings:
· Alignment condition: voltage: 50 V, time: 50 sec.
• Membrane breaking at: voltage: 3000 V, time: 30 μβεΰ
• Post- fusion holding time: 3 sec
After ECF, the cell suspensions were carefully removed from the fusion chamber under sterile conditions and transferred into a sterile tube containing the same volume of Hybridoma Culture Medium (DMEM, JRH Biosciences), 15 % FBS (Hyclone), supplemented with L- glutamine, pen/strep, OPI (oxaloacetate, pyruvate, bovine insulin) (all from Sigma) and IL-6 (Boehringer Mannheim). The cells were incubated for 15-30 minutes at 37°C, and then centrifuged at 400 x g (1000 rpm) for five minutes. The cells were gently resuspended in a small volume of Hybridoma Selection Medium (Hybridoma Culture Medium supplemented with 0.5x HA (Sigma, cat. # A9666)), and the volume adjusted appropriately with more Hybridoma Selection Medium, based on a final plating of 5xl06 B cells total per 96-well plate and 200 μΐ per well. The cells were mixed gently and pipetted into 96-well plates and allowed to grow. On day 7 or 10, one-half the medium was removed, and the cells re-fed with Hybridoma Selection Medium.
Hybridomas were grown as routine in the selective medium. Exhaustive supernatants collected from the hybridomas were tested in various assays as described in Examples 4-5. Just to note, antibodies that begin with a 3 digit, e.g., 3.15G8, are IgG4 and antibodies that begin with a 2, e.g., 2.9D10, are IgG2. EXAMPLE 4: BINDING TO CELL BOUND HUMAN AND CYNOMOLGUS MONKEY
B7-H1
Supernatants collected from hybridoma cells were tested to assess the ability of the secreted antibodies to bind to 293T cells transiently expressing either full length human or cynomolgus monkey B7-H1. A mock-transfected 293T cell line was used as a negative control. Cells diluted in PBS containing 2% FBS were seeded at a density of 2500-3000 expressing and 15000-17500 mock transfected cells in 40 μΐ/well in 384 well plates (Corning Costar, catalog # 3712). Immediately after plating, 10 μΐ/well of hybridoma supernatants were added and plates incubated for 1.5 hr at room temperature. Next, 10 μΐ/well of Cy5 -conjugated goat anti-human IgG Fc (700 ng/ml, Jackson Immunoresearch, catalog # 109-175-098) were added and plates incubated for 3 h at room temperature prior to reading the fluoresence signal on the FMAT 8200 instrument (Applied Biosystems). The results for 6 hybridoma supernatants are shown in Table 3.
Table 3. Binding of hybridoma supernatants to cell-bound human or cynomologus B7-H1
Figure imgf000089_0001
EXAMPLE 5: INHIBITION OF B7-H1/PD-1 RECEPTOR-LIGAND BINDING
To determine the relative potency of the antibody containing supernatants, their ability to inhibit the binding of human PD-l/Fc protein to human B7-H1 expressed on surface of CHO cells was evaluated. 25000 cells/well were plated in 50 μΐ of media into wells of a 384-well tissue culture plate (Corning Costar, catalog # 3712). Next day, 50 μΐ/well of diluted (1 :5) hybridoma supernatant was added and plates were incubated at 4C for 1 hour on a shaker. Biotinylated human PD-l/Fc protein (R&D Systems, catalog #1086-PD) was added to a final concentration of 1.25 ug/ml and plates were incubated at 4C for 1 hour on a shaker. Cells were washed and fixed in 100 ul of PBS containing 3.7% formaldehyde and 3% bovine serum albumin for 20 min at room temperature. Cells were washed and incubated in 100 ul of PBS containing 0.6% H202 and 3% bovine serum albumin for 10 min at room temperature. Cells were washed and incubated in 50 μΐ of horseradish peroxidase-conjugated streptavidin diluted at 1 :4000 for 30 min at 4oC. Cells were washed before signal detection. Data are represented as the percentage of (ODmax- ODmin), where ODmax is the average value obtained with the cells incubated with irrelevant hybridoma supematants in the presence of biotin-conjugated human PD-l/Fc protein and ODmin is the average value obtained with the cells incubated with irrelevant hybridoma supematants in the absence of biotin-conjugated human PD-l/Fc protein. 0% of maximum response indicates 100% inhibition of B7-H1/PD-1 binding by a hybridoma supernatant (Table 4).
Table 4. Inhibition of human PD1 binding to human B7-H1 expressing cells by hybridoma supematants
Figure imgf000090_0001
EXAMPLE 6: BINDING OF PURIFIED ANTI-B7-H1 ANTIBODIES TO HUMAN B7-
Hl, HUMAN B7-DC, MOUSE B7-H1
The ability of the purified antibodies to bind to human B7-H1, B7-DC, mouse B7H1 and cynomolgus monkey B7-H1 was determined by FACS analysis. Briefly, 293T cells were either mock-transfected or transiently transfected with either human B7-H1 or human B7-DC using Lipofectamine 2000 (Invitrogen, catalog #11668). Mouse J558 cells expressing mouse B7-H1 were obtained from ATCC (catalog #TIB-6). Cells were resuspended in PBS containing 2%> FBS (FACS buffer) and seeded at 50000 cells/well into V-bottomed plates. Anti-B7-Hl and isotype control antibodies diluted in FACS buffer were added at a final concentration of 5 μg/ml and plates were incubated for 1 h at 4 °C. After washing with FACS buffer, goat anti-human Fc Cy5 (5 μg/ml, Jackson Immunoresearch, catalog # 109-175-098) and 7-AAD (5 μg/ml) were added and plates were incubated for 15 min at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Table 5 shows ability of purified antibodies (5 μg/ml) to bind to 293T cells transfected with human B7-H1. None of the selected antibodies bound to 293T cells transfected with human B7-DC or to J558 cells that express mouse B7-H1. Mouse anti-human B7-DC (PD-L2) antibody (R&D systems cat #MAB1224, detected with goat anti-mouse Fc Cy5, Jackson Immunoresearch) was used as a positive control for B7-DC expression. PE-conjugated rat anti-mouse B7-H1 antibody (eBioscience, clone M1H5, detected with goat anti-rat Fc Cy5, Jackson
Immunoresearch) was used as a positive control for mouse B7-H1 expression.
Table 5. Binding of purified anti-B7-Hl antibodies to cell-bound human B7-H1, mouse B7- Hl or human B7-DC
Figure imgf000091_0001
EXAMPLE 7: BINDING OF PURIFIED HUMAN ANTI-B7-H1 ANTIBODIES TO STIMULATED HUMAN AND CYNOMOLGUS MONKEY T CELLS
96-well high binding plates were incubated with 100 ul/well of anti-CD3 antibody diluted at 1 ug/ml in PBS (OKT3 clone, eBioscience, catalog # 160037) at 4C overnight. Human T cells were isolated from frozen leukopack using T cell enrichment kit (StemCell Technologies, catalog #19051). Anti-CD3 mAb coated plates were washed with PBS and purified T cells were added in 200 ul of ICM media at 360000 cells/well and cultured for 72 hours. T cells were then harvested, washed in FACS buffer and mixed with diluted purified anti-B7-Hl antibodies or irrelevant human IgG2 or IgG4 antibodies at final concentration of lug/ml in 96-well V-bottom assay plate (50 ul/well). After 2 hours incubation at 4C, T cells were washed twice in FACS buffer and then stained with Cy5 -conjugated goat anti-human IgG Fc antibody (5 ug/ml, Jackson Immunoresearch, catalog # 109-175-098) and 7-AAD (10 ug/ml). Cells were incubated for 30 min at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Live lymphocyte population was selected for analysis based on forward and side scatter as well as negative staining for 7-AAD.
For activation of cynomolgus monkey T cells 96-well high binding plates were incubated with 100 ul/well of goat anti-mouse IgG Fc antibody diluted at 1 ug/ml in PBS at 4C overnight. Plates were washed with PBS and incubated with anti-CD3 antibody diluted at 1 ug/ml in ICM media (clone SP-34, BD catalog #556610) at 37C for 2 hours. Cynomolgus monkey PBMC were isolated from peripheral blood (Bioreclamation, catalog #CYNWBCPT). Anti-CD3 mAb coated plates were washed with PBS and isolated PBMC were added in 200 ul of ICM media at -200000 cells/well and cultured for 72 hours. Cells were then harvested, washed in FACS buffer and mixed with diluted purified anti-B7-Hl antibodies or irrelevant human IgG2 or IgG4 antibodies at a final concentration of lug/ml in 96-well V-bottom assay plate (50 ul/well). After 2 hours incubation at 4C, cells were washed twice in FACS buffer and then stained with Cy5- conjugated goat anti-human IgG Fc antibody (5 ug/ml, Jackson Immunoresearch, catalog # 109- 175-098), FITC-conjugated anti-CD3 antibody (diluted 1 :25, Biospecialty) and 7-AAD (10 ug/ml). Cells were incubated for 1 hour at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Monkey T lymphocyte population was selected for analysis based on forward and side scatter as well as positive staining for CD3 marker and negative staining for 7-AAD. Table 6 shows the ability of purified anti-B7-Hl antibodies (1 μg/ml) to bind to activated human T cells as well as to activated cynomolgus monkey T cells.
Table 6. Binding of purified anti-B7-Hl antibodies to stimulated human or cynomologus T- cells
Figure imgf000092_0001
Figure imgf000093_0001
EXAMPLE 8: INHIBITION OF B7-H1/PD-1 RECEPTOR-LIGAND BINDING
The ability of purified human anti-B7-Hl antibodies to inhibit the binding of human PD-l/Fc protein to human B7-H1 expressed on surface of ES-2 cells (ATCC, catalog # CRL-1978) was evaluated. Briefly, 50000 cells/well were plated in 50 μΐ of PBS into wells of a 384-well tissue culture plate (Corning Costar, catalog # 3712). Next, 50 μΐ/well of a diluted monoclonal antibody was added at final concentration of 2.5, 0.5, 0.1, 0.02, 0.004, 0.008, 0.00016 nM and plates were incubated at 4C for 1 hour. Cells were washed twice and 100 μΐ/well of biotinylated human PD-l/Fc protein (10 ug/ml, R&D Systems, catalog #1086-PD) was added and plates were incubated at 4C for 1 hour.
Cells were washed once and 100 μΐ/well of Cy5 -conjugated streptavidin was added and plates were incubated at 4C for 15 min before being washed again with PBS containing 2% FCS and being read on a FACSCalibur instrument. Some wells were incubated with irrelevant human IgG2 and IgG4 monoclonal antibodies with or without biotin- conjugated human PD-l/Fc to set minimal (0%) and maximal (100%) level of B7- Hl/PD-1 binding inhibition. The percentage of the inhibition in relation to the antibody concentration was analyzed using curve fit tool (GraphPad Prism software) to calculate IC50 value for each antibody, which are shown in table 7.
Table 7. Inhibition of human PDl binding to human B7-H1 expressing ES-2 cell by purified anti-B7-Hl antibodies
Figure imgf000093_0002
3.18G1 0.140
EXAMPLE 9: DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES
ON PROLIFERATION OF CD4 T CELLS
It has been demonstrated that B7-H1 protein co-presented with anti-CD3 antibody on beads inhibits CD3-mediated T cell activation (Freeman et al, J. Exp. Med., 2000, 192 (7): 1027- 1034; Bennet et al, The Journal of Immunology, 2003, 170: 711-718). The ability of purified human monoclonal anti-B7-Hl antibodies to interfere with B7-H1 -mediated suppression of T cell activation was determined as follows.
Briefly, 5x10(8) beads/ml of washed tosyl-activated Dynabeads M-450 (Invitrogen, Cat#
140.13) were coated with 50 ug/ml of mouse anti-human CD3 antibody (BD Bioscience, Cat# 555329) in 0.1 M sodium phosphate buffer (pH 7.4-8.0) at 37°C for 24 hours with shaking. 4x10(8) of CD3-coated beads/ml were further coupled with recombinant human IgGlFc (R&D Systems, cat# l lO-HG-100) at 160 ug/ml or with the recombinant human B7-Hl/Fc protein (R&D Systems, Cat# 156-B7-100) at 80 ug/ml combined with the human IgGlFc protein at 80 ug/ml (total concentration 160 ug/ml) and incubated at 37°C for 24 hours with shaking. The beads were then incubated in PBS containing 0.05% bovine serum albumin at room temperature for 1 hour, washed four times in 0.1% BSA and 2mM EDTA in PBS (pH7.4) and finally resuspended in RPMI1640 media containing 10% FBS at 5x10(7) beads/ml.
Peripheral blood monocytes were isolated from a leukapheresis pack using Ficoll-Paque
Plus (GE Healthcare 17-1440-03) density gradient centrifugation, resuspended in serum-free RPMI 1640 (Gibco 22400-089), and CD4+ T-cells were isolated from PBMC using Dynal CD4 Negative Isolation Kit (Invitrogen, cat# 113-37D) per manufacturer's instructions. 10 ul of coated beads were mixed 10 ul of diluted anti-B7-Hl or control IgG2/4 antibody in a sample tube and incubated at RT for 3-4 hours on a shaker. Purified CD4+ T cells were plated at 10(5) cells/80 ul/well in 96-well plate (Corning, cat#3603) and bead-antibody mix was added at 20ul/well to a total volume of 100 ul/well. T cell activation in the absence of B7-H1 inhibitory effect was determined using beads coated with anti-CD3 antibody and the human IgGlFc protein. Cells were cultured for 5 days and supernatants were harvested and analyzed for IFN-γ release by using BD Human IFN-γ ELISA Kit II (BD Cat. No.550612) per manufacturer's instructions. Cell proliferation was measured on day 5 by the addition of ΙΟμΙ/well of AlamarBlue (Invitrogen DAL 1025). Cells were incubated for 5 hours, and the fluorescence was quantitated on a SpectraMax Gemini EM spectrophotometer with an excitation wavelength of 545nm and an emission wavelength of 600nm. Data are represented as the percentage of ODmax, where ODmax is the average value obtained with T cells activated with anti-CD3/IgGlFc beads. See Figure 1.
EXAMPLE 10: DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON ACTIVATION OF CD4 T CELLS IN DENDRITIC CELL-T-CELL MIXED
LYMPHOCYTE ASSAY
Enhancement of T cell activation by antibodies directed against B7-H1 was determined in a dendritic cell-T-cell mixed lymphocyte (DCMLR) assay. Dendritic cells were generated from monocytic precursors as described previously (Curr Protoc Immunol. 2001 May; Chapter 7: Unit 7.32). Peripheral blood monocytes were isolated from a leukapheresis pack using Ficoll-Paque Plus (GE Healthcare 17-1440-03) density gradient centrifugation, resuspended in serum-free RPMI 1640 (Gibco 22400-089), and allowed to adhere to T150 cell culture flasks (Corning 430825). After 1 hour at 37°C, the nonadherent cells were removed and the cells were cultured in RPMI supplemented with 5% human serum (Invitrogen 34005100). Cytokines were added at a final concentration of 2ng/ml GM-CSF (BD Biosciences 550068) and lOng/ml IL-4 (BD Biosciences 554605). Fresh media with cytokines was added every 2 - 3 days. At day 6 of culture, cells were matured with 20ng/ml of TNF-a (BD Biosciences 554618) and allowed to incubate for 24 hours. Mature dendritic cells were harvested, phenotyped, and frozen for later use.
CD4+ T-cells were isolated from PBMC using a magnetic isolation kit (Dynal 113.17) per manufacturer's instructions and cultured in a primary MLR as described previously (J Immunol. 2003 Apr l;170(7):3637-44). 1.5E5 allogeneic CD4+ responding T-cells were cultured in 96 well-flat bottom microtiter plates (Costar 3595) with dendritic cells at a T-cell: dendritic cell ratio of 1 :2.5. Dendritic cell preparations were treated with 100μg/ml of mitomycin C (Sigma M4287) prior to addition to coculture to prevent any proliferation from contaminating lymphocytes. Antibodies were added at various concentrations in a final volume of 200μ1 of RPMI + 10% human serum. Thymidine incorporation was measured on Day 5 by a 16-h pulse with [3H] thymidine (Ιμ ΛνεΙΙ, Perkin-Elmer NET027001MC). Supernatants were harvested prior to radioactive labeling and analyzed for IFN-γ release by Luminex assay (BioRad 171 -Bl 1921) per manufacturer's instructions. Enhancement of T-cell proliferation by anti-B7-Hl antibodies from repeat experiments is shown in Figure 2. Corresponding IFN-γ release is shown in Figure 3.
EXAMPLE 11: STRUCTURAL ANALYSIS OF B7-H1 ANTIBODIES
The heavy chain variable domain sequences and the light chain variable domain sequence s of the antibodies were sequenced to determine their DNA sequences. The complete sequence information for the anti-B7-Hl antibodies is provided in the sequence listing with nucleotide and amino acid sequences for each gamma and kappa or lambda chain combination. The variable heavy sequences were analyzed to determine the VH family and the J-region sequence. The sequences were then translated to determine the primary amino acid sequence and compared to the germline VH and J-region sequences to assess somatic hypermutations.
Tables 8 and 9 are tables comparing the antibody heavy chain regions to their cognate germline heavy chain region and the antibody light chain regions to their cognate germline light chain region. The amino acid numbering is by numerical numbering.
Immunoglobulin genes undergo various modifications during maturation of the immune response, including recombination between V, D and J gene segments, isotype switching, and hypermutation in the variable regions. Recombination and somatic hypermutation are the foundation for generation of antibody diversity and affinity maturation, but they can also generate sequence liabilities that may make commercial production of such immunoglobulins as therapeutic agents difficult, or increase the immunogenicity risk of the antibody. In general, mutations in CDR regions are likely to contribute to improved affinity and function, while mutations in framework regions may increase the risk of immunogenicity. This risk can be reduced by reverting framework mutations to germline, while ensuring that activity of the antibody is not adversely impacted. Some structural liabilities may be generated by the diversification processes, or they may exist within germline sequences contributing to the heavy and light chain variable domains. Regardless of the source, it may be desirable to remove potential structural liabilities that may result in instability, aggregation, heterogeneity of product, or increased immunogenicity. Examples of undesirable liabilities include unpaired cysteines (which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation), N-linked glycosylation sites (resulting in heterogeneity of structure and activity), as well as deamidation (e.g. NG, NS), isomerization (DG), oxidation (exposed methionine), and hydrolysis (DP) sites.
In order to reduce the risk of immunogenicity, and improve pharmaceutical properties of lead antibodies, it may be desirable to reduce the number of mutations from germline and/or remove structural liabilities.
Thus, in one embodiment, where a particular antibody differs from its respective germline sequence at the amino acid level, the antibody sequence can be mutated back to the germline sequence. Such corrective mutations can occur at one, two, three or more positions, or a combination of any of the mutated positions, using standard molecular biological techniques. Tables 10-14 below illustrate the positions of such variations back to germline for mAb 2.9D10, 2.7A4 and 2.14H9. Each row represents a unique combination of germline and non-germline residues at the position indicated by bold type. The position of the amino acid is representated by numerical numbering.
In another embodiment, the invention includes replacing any structural liabilities in the sequence that might affect the heterogeneity of the antibodies of the invention. Such liabilities include glycosylation sites, un-paired cysteines, surface exposed methinones, etc. To reduce the risk of such heterogeneity it is proposed that changes are made to remove one or more of such structural liabilities.
In one embodiment, it may be desirable to remove one or more consensus N-linked glycosylation sites from the antibody germline or antibody sequence. One skilled in the art would be readily able to identify such a glycosylation site. Typically an N-linked glycosylation consensus site sequence has the sequence of Asn-any AA- Ser or Thr where the middle amino acid cannot be a proline (Pro). In another example, unpaired cysteines can be replaced alone or in conjunction with other structural changes. An unpaired cysteine can be mutated to an appropriate amino acid that has comparable side chain properties such as a serine.
As referred to herein, a sequence that is optimized is a sequence which has been mutated at one or more positions back to its germline sequence or can be modified to remove one or more other liabilities such as structural liabilities. An optimized sequence can also include a sequence that has been mutated at one or more positions back to its germline sequence and which has also been further modified to remove one or more structural liabilities. Heavy V D J FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 chain
EVQLVESGGGLVQPGGSL WVRQAPGKGLEW NIKQDGSEKYYV RFTISRDNAKNSLYLQMNSL ###WFGEL
Germline RLSCAAS GFTFSSY MS VA DSVKG RAEDTAVYYCAR #FDY WGQGTLVTVSS
JH4B
2.14H9 VH3-7 D3-10 -- A
EVQLVESGGGLVQPGGSL WVRQAPGKGLEW NIKQDGSEKYYV RFTISRDNAKNSLYLQMNSL #QL###YF
Germline RLSCAAS GFTFSSYWMS VA DSVKG RAEDTAVYYCAR DY WGQGTLVTVSS G p V—YSD—
3.15G8 VH3-7 D6-6 JH4B --
EVQLVESGGGLVQPGGSL WVRQAPGKGLEW NIKQDGSEKYYV RFTISRDNAKNSLYLQMNSL DWNYYYYG
Germline RLSCAAS GFTFSSYWMS VA DSVKG RAEDTAVYYCAR MDV WGQGTTVTVSS G_Q___
2.9D10 VH3-7 Dl-1 JH6B -- D
EVQLVESGGGLVKPGGSL WVRQAPGKGLEW SISSSSSYIYYA RFTISRDNAKNSLYLQMNSL ###TAMV#
Germline RLSCAAS GFTFSSYSMN VS DSVKG RAEDTAVYYCAR FDY WGQGTLVTVSS GD p DLV-S—
2.7A4 VH3-21 D5-5 JH4B -- A
EVQLLESGGGLVQPGGSL WVRQAPGKGLEW AISGSGGSTYYA RFTISRDNSKNTLYLQMNSL ###YDSSG
Germline RLSCAAS GFTFSSYAMS VS DSVKG RAEDTAVYYCAR ##DY WGQGTLVTVSS
DLH
2.20A8 VH3-23 D3-22 JH4B -- YL—
Figure imgf000099_0001
Table 8
5
Light V J
Chain I. FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4
Germline
GIPDRFSGSGSGIDFILI
EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPRLLIY GASSRAI ISRLEPEDFAVYYC QQYGS##WI FGQGIKVEIK
A27 JK1
2.14H
9 LP—
Germline
GIPDRFSGSGSGIDFILI
EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPRLLIY GASSRAI ISRLEPEDFAVYYC QQYGSS#FI FGPGIKVDIK
A27
2.9D 1
0 JK3 F F T
Germline
GVPSRFSGSGSGIDFILI
DIQMTQSPSSVSASVGDRVTITC RASQGISS LA WYQQKPGKAPKLLIY AASSLQS ISSLQPEDFAIYYC QQANSFPPI FGQGIKVEIK
L5 JK1
3.15G
—SH-L
Germline
GVPSRFSGSGSGIDFILI
DIQMTQSPSSVSASVGDRVTITC RASQGISS LA WYQQKPGKAPKLLIY AASSLQS ISSLQPEDFAIYYC QQANSF##I FGGGIKVEIK
JK4
2.20A
L5 -I-R PL
Germline
GIPERFSGSSSGIMAILI YSIDSSGNHR
SYELTQPPSVSVSPGQTARITC SGDALPKKYAY WYQQKSGQAPVLVIY EDSKRPS ISGAQVEDEADYYC V FGGGIKLIVL
Figure imgf000100_0001
Table 10. Exemplary Mutations of 2.7A4 Heavy Chain (SEQ ID NO: 2) to Germline at the Indicated Residue Number
Figure imgf000101_0001
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2. In certain embodiments, SEQ ID NO.: 2 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments, SEQ ID NO: 2 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 10. In certain embodiments, SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In one specific example, the non germline sequence is mutated back to germline at position 80 where F is changed to a Y and at position 87 where K is changed to an R. A specific example of such a sequence is 2.7A4VHOPT as shown in Table 15.
Table 11: Exemplary Mutations of 2.7A4 Light Chain (SEQ ID NO: 7) to Germline at the Indicated Residue Number
Figure imgf000102_0001
Figure imgf000103_0001
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7. In certain embodiments, SEQ ID NO.: 7 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 11. In some embodiments, SEQ ID NO: 7 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 11. In certain embodiments, SEQ ID NO.: 7 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11. Specific examples of 2.7A4 variable light domain which has been mutated to particular germline sequences include 2.7A4 VLOPT (optimized where the non- germline sequence has been mutated from an A to a T at position 17 and a R to a K at position 104) as shown in Table 15.
Table 12. Exemplary Mutations of 2.9D10 Heavy Chain (SEQ ID NO: 12) to Germline at the Indicated Residue Number
Figure imgf000103_0002
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12. In certain embodiments, SEQ ID NO.: 12 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 12. In some embodiments, SEQ ID NO: 12 comprises any one, any two, or all two of the germline residues as indicated in Table 12. In certain embodiments, SEQ ID NO.: 12 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 12.
Table 13. Exemplary Mutations of 2.9D10 Light Chain (SEQ ID NO: 17) to Germline at the Indicated Residue Number
Figure imgf000104_0001
s Y F T
N Y F T
S F F T
N F F T
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17. In certain embodiments, SEQ ID NO.: 17 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 13. In some embodiments, SEQ ID NO: 17 comprises any one, any two, any three, any four, or all four of the germline residues as indicated in Table 7. In certain embodiments, SEQ ID NO.: 17 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 13. SEQ ID NO: 17 can be altered or further altered by making nongermlining changes to SEQ ID NO: 17. In one example, SEQ ID NO: 17 can be altered such that from a F to a Y at position 37 and from a F to a Y at position 50.
Table 14. Exemplary Mutations of 2.14H9 Light Chain (SEQ ID NO: 27) to Germline at the Indicated Residue Number
Figure imgf000105_0001
In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27. In certain embodiments, SEQ ID NO.: 27 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 14. In some embodiments, SEQ ID NO: 27 comprises any one, any two, any three, or all three of the germline residues as indicated in Table 14. In certain embodiments, SEQ ID NO.: 27 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 14. Specific examples of 2.7A4 variable light domain which has been mutated to a particular germline sequence including 2.14H90PT (optimized where the non- germline sequence has been mutated from an E to a K at position 104) as shown in Table 15.
The heavy chain of 2.14H9 can be changed at amino acid 31 of SEQ ID NO:22 from a R to a S.
Figure imgf000107_0001
Table 15
Ex a B7- 5 HI ces in sest ge Hl ant (F e & Wi be 10 ch
Ta
Ta
Figure imgf000108_0001
2.14H9 Light Chain VK3 (A27) JK1
frameworks of the VH domain and 2 changes in VL domain, located at Kabat number at Kabat numbers 36 and 49 (or numerical numbering residues 37 and 50) . However, those 2 residues are located at Vernier position and have not been mutated to not alter the CDR loop structures. Table 18: Example of residues mutated during germlining for anti-B7-Hl V domains. Residues are numbering according to Kabat nomenclature
Figure imgf000109_0001
Germlining of these amino acid residues was carried out using standard site directed mutagenesis techniques with the appropriate mutagenic primers. The germlined sequences have the prefix "OPT" after the antibody name, for example, 2.7A4VHOPT, 2.7VLOPT and 2.14H9VLOPT. Germlined IgG were then re-evaluated in the human B7-Hl/hPDl ligand inhibition assay to confirm there had not been a reduction in antibody in vitro activity.
Example activities for germlined versus non-germlined anti-B7-Hl antibodies are provided in Figure 4.
Example of gene synthesis and reformatting as IgGl and IgGl-TM Clones were converted from scFv to IgG format by sub-cloning the VH and VL domains into vectors expressing whole antibody heavy and light chains respectively. The VH domains were cloned into the vector pEU15.1 to express IgGl or the vector pEU15.1-TM to express IgGl-TM antibodies. Both vectors contain the human heavy chain constant domains and regulatory elements to express whole IgG heavy chain in mammalian cells. The vector pEU15.1- TM is a modified pEU15.1 human IgGl vector. It was engineered to introduce the three mutations; L234F and L235E in the hinge and P331S in the CH2 domain of the IgG molecule to eliminate its ability to trigger antibody-dependent cell-mediated cytotoxicity and complement- dependent cytotoxicity (Oganesyan V. et al. (2008), Acta Cryst., D64: 700-704). Vector engineering was performed using standard site directed mutagenesis techniques with the appropriate mutagenic primers.
The VL domains were cloned into pEU4.4 and pEU3.4 vectors for the expression of the human lambda and kappa light chain constant domains respectively, with regulatory elements to express whole IgG light chain in mammalian cells. Vectors for the expression of heavy chains and light chains were originally described in Vaughan et al. (Nature Biotechnology 14(3):309- 314, 1996). These vectors have been engineered simply by introducing an OriP element.
To obtain IgGs, the heavy and light chain IgG expression vectors were transfected into EBNA-HEK293 mammalian cells (Invitrogen R620-07). IgGs were expressed and secreted into the medium. Harvests were pooled and spun down prior to purification. The IgG was purified using Protein A chromatography using an AKTA Express purification system (GE Healthcare) previously sanitised to avoid any endotoxin contamination of the sample. Culture supernatants are loaded onto lmL HiTrap™ MabSelectSure™ columns (GE Healthcare, 11-0034-93) and washed with 50 mM Tris-HCl pH 8.0, 250 mM NaCl. Bound IgG was eluted from the column using 0.1 M Sodium Citrate (pH 3.0) and neutralised by the addition of 1M Tris-HCl (pH 9.0). The eluted material was buffer exchanged into PBS using Nap 10 columns (Amersham, 17-0854- 02) and filtered before determining protein concentration and endotoxin levels. IgG concentration was determined spectrophotometrically using an extinction coefficient based on the amino acid sequence of the IgG (Vaughan et al. supra). Endotoxin level was determined using the Endosafe PTS Portable Test System (Charles River Laboratories) fitted with 1-0.1 EU/mL and 10- O.lEU/mL LAL cartridges (Charles River Laboratories, PT520). The purified IgG were analysed for degradation by SDS-PAGE.
Anti-B7-Hl antibodies in the IgGl-TM format were evaluated and compared to the same antibodies but in the IgGl format in the human B7-Hl/hPDl ligand inhibition assay to confirm there had not been a reduction in antibody in vitro activity due to IgG isotype switching (Figure 4)·
EXAMPLE 12: HUMAN B7H1/FC BINDING HUMAN PD1/FC - HTRF® ASSAY
The assay described is a homogenous TR-FRET assay using HTRF® assay technology requiring no wash steps. To a Costar 3676 microtitre plate 5μ1Λνε11 of biotinylated PDl/Fc at InM diluted into PBS was added. This was followed with the addition of 5μ1Λνε11 streptavidin XLent (CisBio) at 4nM diluted into assay buffer (PBS + 0.1% BSA + 0.8M KF). 5μ1Λνε11 of a titration of sample material diluted in PBS was added to relevant wells. For the definition of total binding, 5μ1 of PBS or relevant sample buffer was added per well. To define non-specific binding, an excess (600nM) of unlabelled B7H1/Fc or PDl/Fc was used. The final process was the addition of 5 μΐ/well of cryptate labelled B7H1/Fc (cryptate label - CisBio, B7H1/Fc - RnD Systems) diluted 1 : 100 into assay buffer. The assay plate was left for 3 hours at room temperature before being read on a HTRF® compatible plate reader.
Example of IC50 determinations in the human PDl/human B7-H1 ligand inhibition assay for anti-B7-Hl antibodies are provided in Table 19. All anti-human B7-H1 antibodies are in the IgGl-TM format.
Table 19. Example of IC50 determination (n=2) in the human PDl/human B7-H1 ligand inhibition assay for anti-B7-Hl IgG
Figure imgf000111_0001
EXAMPLE 13: HUMAN B7H1/FC BINDING HUMAN B7-1/FC - HTRF® ASSAY
The assay described was a homogenous TR-FRET assay using HTRF® assay technology requiring no wash steps. To a Costar 3676 microtitre plate 5μ1Λνε11 of biotinylated B7-1/Fc at 8nM diluted into PBS was added. This was followed with the addition of 5μ1Λνε11 streptavidin XLent (CisBio) at 20nM diluted into assay buffer (PBS + 0.1% BSA + 0.8M KF). 5μ1Λνε11 of a titration of sample material diluted in PBS was added to relevant wells. For the definition of total binding, 5μ1 of PBS or relevant sample buffer per well was added. To define non-specific binding, an excess (200nM) of unlabelled B7H1/Fc or B7-1/Fc was used. The final process was the addition of 5 μΐ/well of cryptate labelled B7H1/Fc (cryptate label - CisBio, B7H1/Fc - RnD Systems) diluted 1 : 100 into assay buffer. The assay plate was left overnight at 4°C before being allowed to recover to room temperature and read on a HTRF® compatible plate reader. Example of IC50 determinations in the human B7-1 /human B7-H1 ligand inhibition assay for anti-B7-Hl antibodies are provided in Table 20. All anti-human B7-H1 antibodies are in the IgGl-TM format. Table 20: Example of IC50 determination (n=2) in the human B7-l/human B7-H1 ligand inhibition assay for anti-B7-Hl IgG
Figure imgf000112_0001
EXAMPLE 14: CROSS REACTIVITY OF ANTI-B7-H1 ANTIBODIES WITH OTHER
IMMUNE CO-MODULATORY PROTEINS
ELISAs were performed to determine the cross-reactivity of the anti-B7-Hl IgGl-TM antibodies for other immune co-modulatory molecules. The ELISAs consisted of coating MaxiSorp plates (NUNC) at 4° C overnight with 250ng per well of the extracellular domain (ECD) of human B7-H1 (R&D Systems, 156-B7), human PD-L2 (R&D Systems, 1224-PL), human B7-H2 (R&D Systems, 165-B7), human B7-H3 (R&D Systems, 1027-B3), human CD28 (R&D Systems, 342-CD), human CTLA-4 (R&D Systems, 325-CT) and human PD1 (R&D Systems, 1086-PD) followed by blocking the plates with PBS containing 3% dried milk powder at room temperature for lh. Murine cross reactivity was also investigated by coating the ECD of murine B7-H1 (R&D Systems, 1019-B7). Biotinylated anti-B7-Hl IgGl-TM diluted at ΙΟΟηΜ in PBS containing 3% dried milk powder, were incubated at room temperature for 2h to allow binding. Bound biotinylated IgGs were detected with europium Nl -labelled streptavidin (Perkin Elmer, 1244-360) at 0.2ug/mL. Control experiment demonstrating antigen coating to the NUNC plate was performed using the commercial antibodies mouse IgG2a anti-human B7-H1 (R&D Systems, MAB156), mouse IgG2b anti-human PD-L2 (R&D Systems, MAB1224), mouse IgG2b anti-human B7-H2 (R&D Systems, MAB165), mouse IgGl anti-human B7-H3 (R&D Systems, MAB1027), mouse IgGl anti-human CD28 (R&D Systems, MAB342), mouse IgG2a anti-human CTLA-4 (Abeam, ab33320), mouse IgG2b anti-human PD1 (R&D Systems, MAB1086) and rat IgG2a anti-mouse B7-H1 (R&D Systems, MAB1019). Primary antibodies were incubated at 5ug/mL in PBS containing 3% dried milk powder for 2h at room temperature. Detection was carried out by incubating the secondary antibody anti-mouse IgG Peroxidase conjugate (Sigma, A2554) or anti-rat IgG Peroxidase conjugate (Sigma, A5795) diluted 1 :5000 in PBS containing 3% dried milk powder for lh at room temperature and subsequent addition of TMB (Sigma, T0440). All eight antigens could be detected on the Maxisorp NUNC plate. Non-specific binding was determined using wells coated with the IgGl isotype control at 5ug/mL. Cross reactivities were calculated at a percent of the specific binding to the antigen relative to human B7-H1.
The cross-reactivity of the 3 anti-B7-Hl IgGl-TM antibodies 2.7A40PT, 2.9D10 and 2.14H90PT to the panel of eight immune co-modulatory antigens were determined in triplicate. At lOOnM of antibody concentration, all three anti-B7-Hl antibodies show no cross reactivity for any of the seven human immune co-modulatory molecules we tested (Figure 5). The IgGl-TM anti-B7-Hl antibody 2.7A40PT displays a measurable cross reactivity for murine B7-H1 with a signal level of 5.3% on average compared to 100% binding to the human B7-H1. The other two anti-B7-Hl antibodies tested, 2.9D10 and 2.14H90PT, do not show any cross reactivity for murine B7-H1 (Figure 5).
EXAMPLE 15: AFFINITY OF ANTI-B7-H1 ANTIBODIES FOR HUMAN AND
CYNOMOLOGUS B7-H1
The binding affinity and kinetic parameters of anti-B7-Hl antibodies in the IgGl-TM format to monomeric human and cynomologus B7-H1 were determined by surface plasmon resonance using a BIAcore T100 instrument (BIAcore, Uppsala, Sweden). In brief, experiments were performed at 25°C using HBS-EP buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% v/v surfactant P20) as running buffer. IgGs were affinity captured on the surface of a CM5 sensor chip (BIAcore) via protein G, which was amine coupled onto the CM5 surface to achieve the density of -500 Response Units (RU), according to the manufacturer's instructions (BIAapplications Handbook, BIAcore). Recombinant monomeric human or cynomologus B7-H1 FlagHisio extracellular domains (ECDs) were used as analytes. Dilutions of B7-H1 ECD (200- 3.12 nM) in the running buffer were injected at a constant flow rate of 100 μΐ/min for 60 seconds. All measurements were baseline corrected by subtracting the sensorgram obtained with the control (activated-deactivated) flow cell, as well as double referenced with blank (zero analyte concentration) injections. Data were analyzed using the T-100 BIAevaluation software package and fitted to a simple 1 : 1 Langmuir binding model with local Rmax and bulk refractive index set to 0. Data were calculated from at least two independent experiments. Mass transport effects were limited by keeping the level of affinity-captured IgGs below 250 RU. Sensorgrams obtained with all tested antibodies could be readily fitted onto the monoexponential 1 : 1 binding model giving excellent fits with Chi2 values consistently < 0.3.
Affinity of anti-B7-Hl antibodies 2.7A40PT and 2.14H90PT for monomeric human B7-
Hl is InM and 175pM respectively (Table 21).
Table 21: Affinity and kinetic parameters analysis of anti-B7-Hl antibodies for binding to human B7-H1
Figure imgf000114_0001
Affinity of anti-B7-Hl antibodies 2.7A40PT and 2.14H90PT for monomeric cynomologus B7-H1 is 835pM and 367pM respectively (Table 22). Those two antibodies are strongly cross reactive for cynomologus B7-H1 as affinities are very close to the ones for human B7-H1.
Table 22: Affinity and kinetic parameters analysis of anti-B7-Hl antibodies for binding to cynomologus B7-H1
Figure imgf000114_0002
Reference Antibody #1 4.64 1.36xl06 0.0063
2.7A40PT 0.835 1.31xl06 0.0011
2.14H90PT 0.367 lxlO6 0.00037
EXAMPLE 16: EPITOPE MAPPING OF ANTI-B7-H1 ANTIBODIES
Epitope mapping was performed to identify human B7-H1 residues involved in the binding of anti-B7-Hl antibodies. The structure of the extracellular domain of human B7H1 in complex with murine PD1 has been previously described in the literature (Lin, D et al, 2008, Proc. Natl. Acad. Sci. USA, Vol. 105, p3011-3016) and reveals that fourteen B7-H1 residues are involved in the binding to PD1 (Table 23). Table 23: Human B7-H1 residues involve in the binding to murine PD1
Amino Acid Position
Phe 19
Thr 20
Asp 26
lie 54
Tyr 56
Gin 66
Arg 1 13
Met 1 15
Ser 1 17
Ala 121
Asp 122
Tyr 123
Lys 124
Arg 125 Anti-B7-Hl antibodies are competing for the binding of human B7-H1 to human PD1 (Example 5, 8 and 12) so they should interact with some of those 14 residues if we assume that there are negligible differences between the B7H1 binding interface to human and mouse PD1 (62% amino acid identity between the two species extracellular domain sequence). Single amino acid B7-H1 mutants will be generated for all the 14 positions described in Table 23. Mutants will be tested for binding to anti-B7-Hl antibodies by phage ELISA and the ability to compete the binding of anti-B7-Hl antibodies to human B7-H1 in HTRF® competition assays. All anti-B7-Hl antibodies described are in the IgGl-TM format. Cloning of the human B7-H1 extracellular domain gene in fusion with bacteriophage gene III for phage display expression
Gene coding for the extracellular domain of the human B7-H1 protein (Uniprot accession number Q9NZQ7, amino acid [19-238]) has been synthetised externally by DNA2.0 Inc. and amplified by PCR using the primers B7H1 FOR (5'-
AAT AATGGCCC AGCCGGCCATGGCCTTT ACCGTGACGGT ACCG-3 ' ) and B7H1 REV (5 '-AATAATGCGGCCGCCCTTTCGTTTGGGGGATGC-3 ') to introduce the Sfi I and Not I restriction sites at 5 ' and 3 ' ends respectively. PCR product has then been directionally cloned in the pCANTAB6 vector (McCafferty J. et al, 1994, Appl. Biochem. BiotechnoL, Vol. 47, pl57- 173) using Sfi I and Not I restriction sites. E. coli strain TGI were transformed with the ligation and individual colonies were screened by sequencing to identify a B7-H1 transformant named B7-Hl_pCANTA6.
Generating and identifying B 7 -HI mutants
B7-H1 mutants have been generated by saturation mutagenesis at all the 14 residues of the PD1 interface using fully randomised NNS primers (Table 24) and the plasmid B7- Hl_pCANTA6 as DNA template. Mutagenesis was performed with the Stratagene's QuickChange Multi Site-Directed Mutagenesis Kit (Catalog #200513) according to the manufacturer's instructions. Mutagenic reactions were used to transform E. coli strain TGI and individual colonies were screened by sequencing to identify B7-H1 variants. A total of 252 variants were identified among the 280 possible (20 amino acids time 14 positions) and cherry picked in 3 96-wells culture plates.
Table 24: Mutagenenic primers used to generate B7-H1 variants
Prinu-r Naint SI-(| I-IK-I-
B7H1 SDM _F 19_ f 5 -GC CGGC CATGGCCN S ACCGTGACGGT AC CGAAAG-3'
B7H1 SDM _T20_ f 5' -GC CGGC CATGGCCTTTN SGTGACGGT ACCGAAAG-3 '
B7H1 SDM _D26_ f 5 -CCGTGACGGTACCGAAAN STTGTATGTGGTGGAGTATGG-3'
B7H1 SDM _I54_ f 5' -GGATCTTGCTGCCCTTN SGTCTACTGGGAAATGGAGGACAAG-3 '
B7H1 SDM _Y56_ f 5 -GGATCTTGCTGCCCTTATCGTCN STGGGAAATGGAGGACAAG-3 '
B7H1 _SDM_Q66_ f 5 -GGAGGACAAGAACATCATCN STTTGTCCATGGAGAGGAGG-3'
B7H1_ SDM_ R1 13 _f 5' -ATGCCGGGGTCTACN STGTATGATCTCTTACGGCGG-3'
B7H1_ SDM_ M115 _f 5' -ATGCCGGGGTC TACCGCTGT NS ATCTC TT ACGGCGG-3 '
B7H1 SDM _S 117_ _f 5' -CTACCGCTGTATGATCN STACGGCGGTGCCG-3'
B7H1_ SDM_ A121 _f 5' -GATCTCTTACGGCGGTNNSGATTACAAACGGATAACC-3 '
B7H1_ SDM_ D122 _f 5' -GATCTCTTACGGCGGTGCCN STACAAACGGATAACC-3'
B7H1_ SDM_ Y123 _f 5' -CGGCGGTGCCGATNNSAAACGGATAACCGTAAAGG-3'
B7H1_ SDM_ K124 _f 5' -CGGCGGTGCCGATTACN SCGGATAACCGTAAAGG-3 '
B7H1_ SDM_ R125 _f 5' -GC GGTGCCGATTACAAAN S ATAACCGT AAAGGTAAACG-3 '
Phage ELISA of B7-H1 mutants for binding to anti-B7-Hl antibodies
Binding of the B7-H1 mutants to anti-B7-Hl antibodies 2.14H90PT, 2.7A40PT or Reference Ab#l have been assessed by phage ELISA after assuring that the B7-H1 extracellular domain in fusion with gene III protein could be displayed at the phage surface. Cherry picked TGI cultures were grown and superinfected with M13K07 helper phage to produce phage particles displaying B7-H1 mutants at their surface. Phage supernatants were blocked in PBS+3% skimmed milk and incubated in NUNC MaxiSorb plates previously coated overnight with lug/mL 2.14H90PT, 2.7A40PT or Reference antibody#l in PBS and blocked with PBS+3% skimmed milk. Bound phages were detected using streptavidin coupled with europium (Perkin Elmer) after incubation with a biotinylated anti-M13 secondary antibody (Progen).
Among the 14 human B7-H1 residues located at the PD1 interface, four are not involved in the binding to any of the three tested anti-B7-Hl antibodies (Asp26, Tyr56, Glu66 and Lysl24). Their replacements by an alanine or a glycine do not significantly affect the binding signal. Based on the phage ELISA data, a total of 28 mutants representative of 2 to 3 key changes for each of the 10 others positions have been selected to confirm their binding profile but using purified proteins. Biochemical competition assays
Extracellular domain of human B7-H1 wild-type and mutants were expressed in bacteria and purified by affinity chromatography as previously described (Bannister D. et ah, 2006, Biotechnology and bioengineering, 94, 931-937).
The HTRF® competition assays measured the binding of anti-B7-Hl antibody to HIS FLAG tagged B7-H1. Titration of non tagged B7-H1 samples, prepared as described above, will compete with HIS FLAG tagged B7-H1 for binding to anti-B7-Hl antibody, leading to a reduction in assay signal. The antibodies 2.14H90PT, 2.7A40PT and Reference antibody#l were used to establish competition assays for characterising the relative binding of purified wild- type or mutants B7-H1. This will confirm which B7-H1 residues are required for antibody binding. 10 μΐ of B7-H1 sample was added to a 384 well low volume assay plate (Corning 3673). This was followed by the addition of 5 of either 0.29nM 2.14H90PT, or 1.15nM 2.7A40PT, or 1.15nM Reference antibody#l conjugated to DyLight649 according to manufacturer's instructions (ThermoFisher, 53051) and 5
Figure imgf000118_0001
of a mixed solution of 0.43nM anti-FLAG cryptate (Cisbio International, 61FG2KLB) and 1.25nM HIS FLAG tagged human B7-H1. Assay plates were incubated for 4 hours at room temperature prior to reading time resolved fluorescence at 620 nm and 665 nm emission wavelengths using an En Vision plate reader (Perkin Elmer).
Three additional B7-H1 residues (Ile54, Serl l7 and Alal21) are not involved in the binding to 2.14H90PT and 2.7A40PT as IC50 of B7-H1 mutants for those residues are similar or marginally modified compared to wild-type B7-H1. Competition data to the 3 anti-B7-Hl antibodies for wild-type and all the other B7-H1 mutants are summarised in the Table 25. Table 25: IC50 in nM in the human B7-H1 competition assays for binding to anti-B7-Hl antibodies
Coi ripetition assay ICW in r M
B7-H1 sample 2.14H90PT IgGLTM 2.7A40PT IgGLTM Reference Ab#1 wild-type B7H1 0.76 2.79 1.89
B7H1 F19A 0.56 No inhibition 27.6
B7H1 F19G 0.56 No inhibition 15.3
B7H1 F19S 0.66 No inhibition 21.6
B7H1 T20A 0.45 No inhibition 2.3
B7H1 T20V 0.64 No inhibition 1.9
B7H1 T20D 0.83 No inhibition 1.9
B7H1 R113A No inhibition 4.6 172
B7H1 R113Y No inhibition No inhibition 3.9
B7H1 R113L No inhibition No inhibition 2
B7H1_M115A 3.9 6.9 86
B7H1_M115G 30.4 4.6 No inhibition
B7H1 M115D No inhibition 5.8 No inhibition
B7H1 D122E 29.6 No inhibition 35.2
B7H1 D122N 15.5 No inhibition 2.5
B7H1 Y123A 232 1.77 No inhibition
B7H1 Y123F 0.5 2.21 No inhibition
B7H1 Y123T 427 2.07 No inhibition
B7H1 R125A No inhibition 3 11.7
B7H1 R125Q No inhibition 2.4 18.4
B7H1 R125S No inhibition 2.7 9.7 Argl 13 and Argl 25 are strongly involved in the binding to 2.14H90PT. Replacement by an Ala or other amino acids (Tyr or Leu at position 113 and Gin or Ser at position 125) lead to a total lost of binding to that antibody. Binding profile of those B7-H1 mutants to 2.7A40PT or Reference antibody#l is similar to the wild-type B7-H1. This shows that the lost of binding is not due to a general structural modification of B7-H1 as for instance an unfolded protein but to a direct involvement of those residues with 2.14H90PT binding. Those data also demonstrate that 2.14H90PT binding epitope is different from 2.7A40PT and Reference antibody#l epitopes. Metl l5, Aspl22 and Tyrl23 are also involved in the binding to 2.14H90PT but to a lesser extend. Replacement of Metl l5 by an Ala does not affect the binding to 2.14H90PT or 2.7A40PT but replacement by an Asn leads to a total lost of binding activity to 2.14H90PT but not to 2.7A40PT. In a similar way, replacement of Asp 122 by an Asn is affecting the binding to 2.14H90PT but not to Reference antibody#l . Mutating Tyrl23 by an Ala or a Thr greatly modify the binding profile to 2.14H90PT but not to 2.7A40PT. Interestingly, a replacement by a Phe does not change the binding to 2.14H90PT suggesting that the hydroxyl group of the tyrosine 123 is not involved in the binding interaction.
Phel9, Thr20 and Aspl22 are strongly involved in the binding to 2.7A40PT. All B7-H1 mutants at those positions have no binding to that antibody but do bind 2.14H90PT or Reference antibody#l in a similar way to wild-type B7-H1, excepted B7H1 D122E mutant which binds those 2 antibodies less efficiently. Those three residues are specifics to the 2.7A40PT mAb binding epitope and are not shared by the 2.14H90PT or the Reference antibody#l epitopes. Argl 13 is also involved in the 2.7A40PT epitope but to a lesser extend. Replacement by an Ala does not affect the binding to that antibody but a Tyr or Leu mutations lead to a total lost of binding. Those mutations at position 113 do not affect the binding to the Reference antibody#l showing that B7-H1 mutants are still in a correct conformation. It is possible that the replacement by a bulky amino acid as a Tyr may introduce some steric hindrances. Those results suggest that the Argl 13 is not directly involved in the contact to the 2.7A40PT antibody but is very close to the actual binding epitope. This example demonstrates that the three anti-B7-Hl antibodies 2.14H90PT, 2.7A40PT and Reference antibody#l have distinct binding epitopes at the B7-H1 interface with PD1. Furthermore, it is possible that those antibodies may also bind to other human B7-H1 residues but which are not located at the PD1 interface.
EXAMPLE 17. DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON A MEMORY T-CELL RESPONSE TO SUB-OPTIMAL CONCENTRATIONS OF A
RECALL ANTIGEN
B7-H1 interaction with PD-1 has been shown to inhibit antigen specific T-cell responses. In order to assess the effect of anti-B7-Hl antibodies on this inhibition a sub-optimal antigen recall assay was performed.
Peripheral blood monocytes (PBMCs) were isolated from human blood buffy coats using Ficoll-Paque Plus (GE Healthcare 17-1440-03) density gradient centrifugation as per manufacturers instructions. Following isolation cells were resuspended in RPMI 1640 Glutamax I media (GIBCO,.61870) supplemented with 1% pen/strep (GIBCO,. 15140) and 4% Human AB Serum (Invitrogen 34005), and then subsequently cultured in 96 well, round bottom tissue culture plates (Corning,.3799) at 370C, 5% C02, with or without O. ^g/mL tetanus toxoid (Calbiochem582231) at a density of 1x105 cells per well. After three days of culture, anti-B7-Hl antibodies in the IgGl-TM format or isotype control were added at the indicated concentrations and cultures returned to 37°C for a further 2 days, at which point supematants were harvested and analysed by DELFIA for levels of interferon-γ. Enhancement of interferon-γ release by anti-B7-Hl antibodies is shown in Figure 6.
Anti-B7-Hl antibodies 2.9D10, 2.7A40PT and 2.14H90PT are able to increase the release of Interferon-γ. This data confirms the ability of 2.9D10, 2.7A40PT and 2.14H90PT to enhance antigen specific T-cell responses.
EXAMPLE 18. DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON A MEMORY T-CELL RESPONSE TO OPTIMAL CONCENTRATIONS OF A
RECALL ANTIGEN B7-H1 has been suggested to have potential inhibitory signalling properties. The potential for anti-B7-Hl antibodies to act as agonist that might drive such inhibitory signalling was tested by examining their ability to inhibit an antigen recall response.
Peripheral blood monocytes (PBMCs) were isolated from a human blood buffy coats using Ficoll-Paque Plus (GE Healthcare 17-1440-03) density gradient centrifugation as per manufacturers instructions. Following isolation cells were resuspended in RPMI 1640 Glutamax I media (GIBCO,.61870) supplemented with 1% pen/strep (GIBCO,. 15140) and 4% Human AB Serum (Invitrogen 34005), and then subsequently cultured, at a density of 1x105 cells per well, in 96 well, round bottom tissue culture plates (Corning,.3799) at 370C, 5% C02, together with 5μg/mL tetanus toxoid (Calbiochem .582231) and in the presence or absence of varying concentrations of anti-B7-Hl antibodies in the IgGl-TM format or isotype control. An antibody against a T-cell co-receptor has been used as positive control. Following 5 days of culture cells were pulsed with 0.5μΟΛνε11 tritiated thymidine for approximately 16 hours in order to assess proliferative activity.
No inhibitory effects were observed with 2.9D10, 2.7A4 and 2.14H9 anti-B7-Hl antibodies, in contrast to positive control, as shown in Figure 7. This suggests that 2.9D10, 2.7A4 and 2.14H9 antibodies are pure antagonists, without any agonistic activity.
EXAMPLE 19. TUMOR GROWTH INHIBITION ACTIVITY OF ANTI-B7-H1
ANTIBODIES
The in-vivo activity of anti-human B7-H1 antibodies was investigated in xenograft mouse models using immunocompromised NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice. The mice were engrafted subcutaneously (SC) with human cancer cell lines expressing human B7-H1 and human CD4+ and CD8+ T cells that were isolated from peripheral blood mononuclear cells of healthy donors and cultured to enrich for alloreactive effector T cells. Intraperiteneal (IP) doses of anti-human B7-H1 antibodies were given to mice inoculated with the human pancreatic cancer cell line HP AC or the human melanoma cell line A375. Effect of the antibodies was observed on tumor growth until a 2000 mm3 tumor volume or gross tumor necrosis. To generate CD4+ and CD8+ T cell lines, human PBMC's from healthy donors were enriched for CD4+ or CD8+ T cells by the addition of 1 mL RosetteSep T cell enrichment product per 20 mL of whole blood. This was followed by a 20-minute incubation and subsequent isolation by density gradient centrifugation using RosetteSep DM-L density medium. After centrifugation, the cells were washed with PBS and resuspended in RPMI 1640 medium supplemented with 10% FBS. Enriched CD4+ and CD8+ T cells were cultured separately for 7- 10 days in medium supplemented with rhIL-2 and each combined with mitomyosin C treated A375 or HP AC cells. T cells were collected and separately cultured again for 7-10 days in medium supplemented with rhIL-2 and combined with mitomyosin C treated A375 or HPAC cells. CD4+ and CD8+ T cells were collected and combined at a 1 : 1 ratio.
A375 and HPAC cancer cell lines and PBMC enriched for CD4+ and CD8+ T cells were mixed immediately before subcutaneous (SC) administration at the indicated effector-to-target (E:T) ratios. The inoculation number of cells for each cancer cell line was predetermined by empirical tumor forming dose studies; in general, 2.5 x 106 cells in a total volume of 0.2 mL were engrafted into each animal.
Six animals were assigned to each experimental group. The animals received an isotype control human IgG2a or IgGlOPT (also referred to herein as "IgGlTM") antibody or the anti- B7-H1 antibodies 2.14H9 IgG2a, 2.14H90PT, 2.7A40PT or Reference antibody#l in the IgGlOPT format. A total of eight independent experiments have been carried out and study designs for each experiment are presented in Tables 26 - 33. Described anti-B7-Hl antibodies are in the IgGlOPT format except where specified.
The first dose (200 μί) of test article was administered IP 1 hour after engraftment of cancer/effector T cells; the animals received up to 4 additional doses of the test article on study days 3, 5, 8 and/or 10. As a positive control to enhance alloreactivity in some studies, rhIL-2 was administered IP 1 hour after engraftment of cancer/effector T cells; the animals received 4 additional daily doses of rhIL-2 for 4 consecutive days. The formation of tumor was observed in each animal one or two times a week. Tumors were measured by caliper; tumor volumes (V) were calculated using the following formula:
V(mm ) = 0.5 (length (mm) x width (mm) x width (mm)/2). For each group, the results are reported as the arithmetic mean. Anticancer effect, expressed as a percent tumor growth inhibition (TGI), was calculated by the following method:
% TGI = [1 - (mean tumor V of treatment group) ÷ (mean tumor V of control group)] x 100.
In Study 1, anti-B7-Hl antibodies 2.14H9 IgG2a and 2.7A40PT significantly inhibited the growth of HP AC (pancreas) cancer cells at day 30 by up to 61% and 50%> respectively as compared to the isotype control group (Figure 8 and Table 26).
Table 26: Study 1 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
Figure imgf000124_0001
NA = not applicable In Study 2, anti-B7-Hl antibodies 2.14H90PT and 2.7A40PT inhibited the growth of HP AC (pancreas) cancer cells at day 39 by up to 70% and 68%> respectively as compared to the isotype control group (Figure 9 and Table 27). Table 27: Study 2 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
Figure imgf000125_0001
NA = not applicable
In Study 3, anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of HPAC (pancreas) cancer cells at day 30 by up to 60%> as compared to the isotype control group (Figure 10 and Table 28).
Table 28: Study 3 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
Figure imgf000126_0001
NA = not applicable In Study 4 anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of HP AC
(pancreas) cancer cells at day 22 by up to 74% as compared to the isotype control group (Figure 11 and Table 29).
Table 29: Study 4 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
Group Test Article Dose (mg/kg/mouse) % TGI at day 22
1 None NA NA
2 None NA NA
3 Human IgGl OPT 5 NA
4 2.14 H90PT 5 74
5 2.14 H90PT 1 55
6 2.14 H90PT 0.1 26
7 2.14 H90PT 0.01 21
In Study 5, IP administration of 2.14H9 IgG2a or 2.70PT anti-B7-Hl antibodies in the A375 (melanoma) xenograft model also significantly inhibited tumor growth at day 29 by as much as 64% and 61% respectively as compared to the isotype control group (Figure 12 and Table 30).
Table 30: Study-5. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies
Group Test Article Dose (mg/kg/mouse) % TGI at day 29
1 None NA NA
2 rhIL-2 105 U/dose NA
3 Isotype human IgG2a 10 NA
4 Isotype human IgG2a 1 NA
5 Isotype human IgG2a 0.1 NA
6 Isotype human IgGlOPT 10 NA
7 Isotype human IgGlOPT 1 NA
8 Isotype human IgGlOPT 0.1 NA
9 2.14H9 IgG2a 10 54
10 2.14H9 IgG2a 1 37
11 2.14H9 IgG2a 0.1 64
12 2.7A40PT 10 21
13 2.7A40PT 1 61
14 2.7A40PT 0.1 55
NA = not applicable
In Study 6, anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 77% as compared to the isotype control group (Figure 13 and Table 31).
Table 31: Study-6. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies Group Test Article Dose (mg/kg/mouse) % TGI at day 25
1 None NA NA
2 None NA NA
3 Human IgGl OPT 5 NA
4 Human IgG 1 OPT; no T 5 NA
cells
5 2.14 H90PT 5 67
6 2.14 H90PT 1 77
7 2.14 H90PT 0.1 72
8 2.14 H90PT; no T cells 1 13
9 2.14 H90PT; no T cells 0.1 25
NA = not applicable
In Study 7, anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 82% as compared to the isotype control group (Figure 14 and Table 32).
Table 32: Study-7. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies
Group Test Article Dose (mg/kg/mouse) % TGI at day 25
1 None NA NA
2 None NA NA
3 Human IgGl OPT 5 NA
4 Human IgG 1 OPT; no T 5 NA
cells
5 2.14 H90PT 5 55
6 2.14 H90PT 1 82
7 2.14 H90PT 0.1 72
8 2.14 H90PT; no T cells 1 36
9 2.14 H90PT; no T cells 0.1 27
NA = not applicable
In Study 8, anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 93% as compared to the isotype control group (Figure 15 and Table 33).
Table 33: Study-8. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies
Figure imgf000130_0001
NA = not applicable These results demonstrated that the anti-human B7-H1 antibodies 2.14H9 IgG2a, 2.14H90PT and 2.7A40PT have potent in vivo anticancer activity in xenograft mouse models of human cancers and provide evidence that those anti-human B7-H1 antibodies can have activity as a single-agent therapy for the treatment of patients with cancers expressing B7-H1.
INCORPORATION BY REFERENCE
All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety. U.S. provisional patent application serial number 61/264,061 filed November 24, 2009, the figures and the sequences therein are hereby incorporated by reference in its entirety.
EQUIVALENTS
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The foregoing description and Examples detail certain preferred embodiments of the invention and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the invention may be practiced in many ways and the invention should be construed in accordance with the appended claims and any equivalents thereof.

Claims

CLAIMS:
1. An isolated antibody that specifically binds to B7-H1, wherein the antibody exhibits one or more of the following properties, selected from the group consisting of:
binds human B7-H1 with a KD of less than 2 nM, as determined by BIAcore;
cross-reacts with cynomologus monkey B7-H1 ;
binds cynomologus B7-H1 with a KD of less than 2 nM, as determined by BIAcore;
exhibits activation of CD4+ T cells in dendritic cell-T-cell mixed lymphocyte assay; inhibits binding of human B7-H1 to PD-1 expressed on ES-2 cells with an IC50 of less than 0.2 nM;
inhibits binding of human B7-H1 to B7-1 using a homogenous TR-FRET assay with an IC50 of less than 0.1 nM; and
inhibits tumor growth of a cancer cell line in a xenograft model as compared to an isotype control antibody.
2. The antibody according to claim 1, wherein said antibody inhibits tumor growth of a human pancreatic cancer (HP AC) cell line in a xenograft model by day 30 by greater than 40% compared to the isotype control, as determined by measuring tumor volumes.
3. The antibody according to claim 1, wherein said antibody inhibits tumor growth of
A375 (melanoma) cell line in a xenograft model by day 30 by greater than 50% compared to the isotype control, as determined by measuring tumor volumes.
4. The antibody according to any one of the preceding claims, wherein the antibody binds to the same epitope on the extracellular domain of human B7-H1 as any one of antibodies
2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
5. The antibody of claim 4, wherein the antibody binds an epitope on the extracellular domain of human B7-H1 comprising at least two of the following three amino acid residues of Asp at position 122, Arg at position 125 or Arg at position 113.
6. The antibody of claim 5, wherein the antibody exhibits no binding to an epitope comprising He at position 54, Ser at position 117, and Ala at position 121 on human B7-H1, as determined by a competition assay.
7. The antibody of claim 5, wherein the antibody loses its ability to bind to human
B7-H1 if the Arg at position 113 on said human B7-H1 is mutated to an Ala, or to a Tyr, or to a Leu, as determined by a competition assay as compared to binding to wild-type B7-H1.
8. The antibody of claim 5, wherein said antibody loses its ability to bind to human B7-H1 if the Arg at position 125 on said human B7-H1 is mutated to an Ala, or to a Gin, or to a
Ser, as determined by a competition assay as compared to binding to wild-type B7-H1.
9. The antibody of claim 5, wherein said antibody retains its ability to bind to human B7-H1 if the Arg at position 123 on said human B7-H1 is mutated to an Ala, or to a Phe, or to a Thr, as determined by a competition assay as compared to binding to wild-type B7-H1.
10. The antibody of claim 4, wherein the antibody binds at least two of the following three amino acid residues of Phe at position 19, Thr at position 20 or Asp at position 122 on human B7-H1.
11. The antibody of claim 10, wherein the antibody exhibits no binding to an epitope comprising He at position 54, Met at position 115, Ser at position 117, and Ala at position 121 on human B7-H1, as determined by a competition assay as compared to binding to wild-type B7-H1.
12. The antibody of claim 10, wherein said antibody loses its ability to bind to human
B7-H1 if the Phe at position 19 on said human B7-H1 is mutated to an Ala, or to a Gly, or to a Ser, as determined by a competition assay as compared to binding to wild-type B7-H1.
13. The antibody of claim 10, wherein said antibody loses its ability to bind to human B7-H1 if the Thr at position 20 on said human B7-H1 is mutated to an Ala, or to a Val, or to a Asp, as determined by a competition assay as compared to binding to wild-type B7-H1.
14. The antibody of claim 10, wherein said antibody loses its ability to bind to human B7-H1 if the Asp at position 122 on said human B7-H1 is mutated to an Asn, or to a Glu, as determined by a competition assay as compared to binding to wild-type B7-H1.
15. The antibody of claim 10, wherein said antibody retains its ability to bind to human B7-H1 if the Arg at position 123 on said human B7-H1 is mutated to an Ala, or to a Phe, or to a Thr, as determined by a competition assay as compared to binding to wild-type B7-H1.
16. The antibody of claim 1, wherein said antibody binds human B7-H1 with a Kd of less than 1.0 nM, as determined by BIAcore.
17. The antibody of claim 16, wherein said antibody binds human B7-H1 with a Kd of less than 200 pM, as determined by BIAcore.
18. The antibody of claim 1, wherein said antibody is a monoclonal antibody.
19. The antibody of claim 18, wherein said antibody is a fully human monoclonal antibody.
20. The antibody according to any one of the preceding claims, wherein said antibody is any one of 2.9D10, 2.7A4, 2.14H9, 2.7A40PT, or 2.14H90PT.
21. The antibody of claim 20, wherein said antibody is a binding fragment selected from the group consisting of a Fab, Fab', F(ab')2, Fv and dAb fragment.
22. The antibody of claim 20 having an amino acid sequence comprising:
a heavy chain variable CDR amino acid sequence encoded by a polynucleotide in a plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 and a light chain variable CDR amino acid sequence encoded by the polynucleotide in a plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598; or a heavy chain variable CDR amino acid sequence encoded by a polynucleotide in a plasmid designated 2.14H9 G which was deposited at the NCIMB under deposit number 41597 and a light chain variable CDR amino acid sequence encoded by the polynucleotide in a plasmid designated 2.14H9 G which was deposited at the NCIMB under deposit number 41597; or
a heavy chain variable CDR amino acid sequence encoded by a polynucleotide in a plasmid designated 2.9D10 NG which was deposited at the NCIMB under deposit number 41599 and a light chain variable CDR amino acid sequence encoded by the polynucleotide in a plasmid designated 2.9D10 NG which was deposited at the NCIMB under deposit number 41599.
23. The antibody of claim 20 having an amino acid sequence comprising:
a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and
a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and
a VL CDR1 having the amino acid sequence of SEQ ID NO: 8; and
a VL CDR2 having the amino acid sequence of SEQ ID NO: 9; and
a VL CDR3 having the amino acid sequence of SEQ ID NO: 10; or a VH CDR1 having the amino acid sequence of SEQ ID NO: 23; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 24; and
a VH CDR3 having the amino acid sequence of SEQ ID NO: 25; and
a VL CDR1 having the amino acid sequence of SEQ ID NO: 28; and
a VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and
a VL CDR3 having the amino acid sequence of SEQ ID NO: 30; or a VH CDR1 having the amino acid sequence of SEQ ID NO: 13; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and
a VH CDR3 having the amino acid sequence of SEQ ID NO: 15; and
a VL CDR1 having the amino acid sequence of SEQ ID NO: 18; and
a VL CDR2 having the amino acid sequence of SEQ ID NO: 19; and
a VL CDR3 having the amino acid sequence of SEQ ID NO: 20; or a VH CDR1 having the amino acid sequence of SEQ ID NO: 63; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 64; and
a VH CDR3 having the amino acid sequence of SEQ ID NO: 65; and
a VL CDR1 having the amino acid sequence of SEQ ID NO: 68; and
a VL CDR2 having the amino acid sequence of SEQ ID NO: 69; and
a VL CDR3 having the amino acid sequence of SEQ ID NO: 70; or a VH CDR1 having the amino acid sequence of SEQ ID NO: 73; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 74; and
a VH CDR3 having the amino acid sequence of SEQ ID NO: 75; and
a VL CDR1 having the amino acid sequence of SEQ ID NO: 78; and
a VL CDR2 having the amino acid sequence of SEQ ID NO: 79; and
a VL CDR3 having the amino acid sequence of SEQ ID NO: 80.
24. The antibody of claims 22 or 23, wherein said antibody further comprises an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, and 33 IS, as numbered by the EU index as set forth in Kabat.
25. A nucleic acid molecule encoding the antibody of claim 24.
26. A host cell transfected with a vector comprising the nucleic acid molecule of claim 25.
27. An antibody produced by a method comprising, culturing said host cell of claim 26, expressing an antibody encoded by said nucleic acid molecule of claim 25, and isolating said antibody from said culture.
28. A composition comprising the antibody of claim 22 or 23 or 24.
29. A pharmaceutical composition comprising the antibody of claim 22 or 23 or 24 and a pharmaceutically acceptable carrier.
30. A method of repressing B7-H1 -mediated T cell inhibition in an animal comprising, administering to an animal in need thereof an effective amount of the composition of claim 28.
31. A method of treating a malignant tumor in an animal, comprising: selecting an animal in need of treatment for a malignant tumor; and administering to said animal a therapeutically effective amount of the composition of claim 29.
32. The method of claim 31, wherein said malignant tumor is selected from the group consisting of: melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, lung cancer, renal cell carcinoma, cervical cancer, colon cancer, colorectal cancer, and pancreatic cancer.
33. The method of claim 30-32, wherein said animal is human.
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Cited By (550)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies 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
WO2014055648A1 (en) 2012-10-02 2014-04-10 Bristol-Myers Squibb Company Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer
WO2015016718A1 (en) 2013-08-02 2015-02-05 Bionovion Holding B.V. Combining cd27 agonists and immune checkpoint inhibition for immune stimulation
WO2015033303A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Cyclic peptidomimetic compounds as immunomodulators
WO2015033299A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015033301A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
WO2015036499A1 (en) * 2013-09-11 2015-03-19 Medimmune Limited Anti-b7-h1 antibodies for treating tumors
WO2015036511A1 (en) * 2013-09-12 2015-03-19 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and antibodies against human pd-l1
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
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
WO2015095423A2 (en) 2013-12-17 2015-06-25 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
WO2015095418A1 (en) 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
JP2015519375A (en) * 2012-05-31 2015-07-09 ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. Antigen binding protein that binds to PD-L1
WO2015112805A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
EP2903641A2 (en) * 2012-10-04 2015-08-12 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-pd-l1 antibodies and methods of use
CN104830788A (en) * 2015-05-05 2015-08-12 杨光华 DC cell based on HBV-HCV antigen, targeting immune cell population, preparation method and applications thereof
KR20150094674A (en) * 2012-12-11 2015-08-19 알버트 아인슈타인 컬리지 오브 메디신 오브 예쉬바 유니버시티 Methods for high throughput receptor:ligand identification
DE202014010421U1 (en) 2013-12-17 2015-11-12 Kymab Limited Human goals
US9192667B2 (en) 2013-04-22 2015-11-24 Hoffmann-La Roche Inc. Method of treating cancer by administering CSF-1R antibodies and a TLR9 agonist
US20150344577A1 (en) * 2013-01-11 2015-12-03 Dingfu Biotarget Co., Ltd Agents for treating tumors, use and method 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
US9212224B2 (en) 2012-05-15 2015-12-15 Bristol-Myers Squibb Company Antibodies that bind PD-L1 and uses thereof
WO2015195163A1 (en) * 2014-06-20 2015-12-23 R-Pharm Overseas, Inc. Pd-l1 antagonist fully human antibody
WO2016007235A1 (en) 2014-07-11 2016-01-14 Genentech, Inc. Anti-pd-l1 antibodies and diagnostic uses thereof
WO2016004876A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Anti-pd-l1 combinations for treating tumors
WO2016011160A1 (en) 2014-07-15 2016-01-21 Genentech, Inc. Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors
US20160031990A1 (en) * 2014-05-29 2016-02-04 Medlmmune, Llc Antagonists of pdl-1 and pd-1 for the treatment of hpv-negative cancers
JP2016504336A (en) * 2012-12-21 2016-02-12 メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. Antibody binding to human programmed death ligand 1 (PD-L1)
WO2016030455A1 (en) 2014-08-28 2016-03-03 Medimmune Limited Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small lung cancer
WO2016034718A1 (en) * 2014-09-05 2016-03-10 Medimmune Limited Methods for identifying patients responsive to anti-pd-l1 antibody therapy using markers (cxcl9, krt8.trim29, and ifngamma)
WO2016081384A1 (en) 2014-11-17 2016-05-26 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
WO2016081748A2 (en) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
WO2016090300A1 (en) 2014-12-05 2016-06-09 Genentech, Inc. Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists
WO2016094481A1 (en) * 2014-12-09 2016-06-16 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized cluster of differentiation 274 gene
WO2016111645A1 (en) * 2015-01-09 2016-07-14 Agency For Science, Technology And Research Anti-pd-l1 antibodies
WO2016127052A1 (en) 2015-02-05 2016-08-11 Bristol-Myers Squibb Company Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy
WO2016142833A1 (en) 2015-03-10 2016-09-15 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators
WO2016146259A1 (en) 2015-03-16 2016-09-22 Amal Therapeutics Sa A novel complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for treatment of glioblastoma
WO2016166348A1 (en) * 2015-04-17 2016-10-20 Elsalys Biotech Anti-tyro3 antibodies and uses thereof
WO2016181349A1 (en) 2015-05-14 2016-11-17 Pfizer Inc. Combinations comprising a pyrrolidine-2,5-dione ido1 inhibitor and an anti-body
WO2016149201A3 (en) * 2015-03-13 2016-11-24 Cytomx Therapeutics, Inc. Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof
WO2016196218A1 (en) 2015-05-31 2016-12-08 Curegenix Corporation Combination compositions for immunotherapy
WO2016196228A1 (en) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Antibodies against ox40 and uses thereof
WO2016196381A1 (en) 2015-05-29 2016-12-08 Genentech, Inc. Pd-l1 promoter methylation in cancer
WO2016196298A1 (en) 2015-05-29 2016-12-08 Genentech, Inc. Therapeutic and diagnolstic methods for cancer
WO2016197204A1 (en) 2015-06-11 2016-12-15 Bionomics Limited Pharmaceutical combination and uses thereof
WO2016200835A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
WO2016201425A1 (en) 2015-06-12 2016-12-15 Bristol-Myers Squibb Company Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways
WO2016205320A1 (en) 2015-06-17 2016-12-22 Genentech, Inc. Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes
WO2017004016A1 (en) 2015-06-29 2017-01-05 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
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
WO2017020858A1 (en) 2015-08-06 2017-02-09 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
US9605070B2 (en) 2014-01-31 2017-03-28 Novartis Ag Antibody molecules to TIM-3 and uses thereof
WO2017058780A1 (en) 2015-09-30 2017-04-06 Merck Patent Gmbh Combination of a pd-1 axis binding antagonist and an alk inhibitor for treating alk-negative cancer
WO2017055484A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for determining the metabolic status of lymphomas
WO2017064043A1 (en) 2015-10-12 2017-04-20 Innate Pharma Cd73 blocking agents
WO2017077382A1 (en) 2015-11-06 2017-05-11 Orionis Biosciences Nv Bi-functional chimeric proteins 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
WO2017087280A1 (en) 2015-11-16 2017-05-26 Genentech, Inc. Methods of treating her2-positive cancer
WO2017087851A1 (en) 2015-11-19 2017-05-26 Genentech, Inc. Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors
WO2017075045A3 (en) * 2015-10-30 2017-06-08 Mayo Foundation For Medical Education And Research Antibodies to b7-h1
EP3178848A1 (en) 2015-12-09 2017-06-14 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies
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
WO2017112741A1 (en) 2015-12-22 2017-06-29 Novartis Ag Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy
WO2017118634A1 (en) 2016-01-04 2017-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma
WO2017125532A1 (en) 2016-01-21 2017-07-27 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
WO2017134305A1 (en) 2016-02-05 2017-08-10 Orionis Biosciences Nv Bispecific signaling agents and uses thereof
WO2017144681A1 (en) 2016-02-25 2017-08-31 Cell Medica Switzerland Ag Binding members to pd-l1
WO2017152085A1 (en) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Combination therapy with anti-cd73 antibodies
WO2017151502A1 (en) 2016-02-29 2017-09-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2017153433A1 (en) 2016-03-08 2017-09-14 Innate Pharma Siglec neutralizing antibodies
WO2017159699A1 (en) 2016-03-15 2017-09-21 Chugai Seiyaku Kabushiki Kaisha Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies
WO2017157964A1 (en) 2016-03-16 2017-09-21 Amal Therapeutics Sa Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine
WO2017167921A1 (en) 2016-03-30 2017-10-05 Centre Léon-Bérard Lymphocytes expressing cd73 in cancerous patient dictates therapy
WO2017175156A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017175147A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017181111A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017181079A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017184619A2 (en) 2016-04-18 2017-10-26 Celldex Therapeutics, Inc. Agonistic antibodies that bind human cd40 and uses thereof
WO2017194782A2 (en) 2016-05-13 2017-11-16 Orionis Biosciences Nv Therapeutic targeting of non-cellular structures
WO2017194783A1 (en) 2016-05-13 2017-11-16 Orionis Biosciences Nv Targeted mutant interferon-beta and uses thereof
WO2017200969A1 (en) 2016-05-20 2017-11-23 Eli Lilly And Company Combination therapy with notch and pd-1 or pd-l1 inhibitors
EP3252078A1 (en) 2016-06-02 2017-12-06 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
WO2017210335A1 (en) 2016-06-01 2017-12-07 Bristol-Myers Squibb Company Imaging methods using 18f-radiolabeled biologics
WO2017220990A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 antibodies
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2018029474A2 (en) 2016-08-09 2018-02-15 Kymab Limited Anti-icos antibodies
WO2018031865A1 (en) 2016-08-12 2018-02-15 Genentech, Inc. Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a vegf inhibitor
WO2018029124A1 (en) 2016-08-08 2018-02-15 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
WO2018049474A1 (en) 2016-09-16 2018-03-22 Bionomics Limited Antibody and checkpoint inhibitor combination therapy
WO2018055060A1 (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
WO2018055145A1 (en) 2016-09-26 2018-03-29 F. Hoffmann-La Roche Ag Predicting response to pd-1 axis inhibitors
WO2018064299A1 (en) 2016-09-29 2018-04-05 Genentech, Inc. Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a taxane
WO2018068028A1 (en) 2016-10-06 2018-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2018065625A2 (en) 2016-10-07 2018-04-12 Enterome Immunogenic compounds for cancer therapy
WO2018065628A2 (en) 2016-10-07 2018-04-12 Enterome Microbiota sequence variants of tumor-related antigenic epitopes
WO2018065623A2 (en) 2016-10-07 2018-04-12 Enterome Immunogenic compounds for cancer therapy
US9957323B2 (en) 2016-06-20 2018-05-01 Kymab Limited Anti-ICOS antibodies
WO2018077893A1 (en) 2016-10-24 2018-05-03 Orionis Biosciences Nv Targeted mutant interferon-gamma and uses thereof
WO2018081621A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Methods of treating urothelial carcinoma using an anti-pd-1 antibody
WO2018085555A1 (en) 2016-11-03 2018-05-11 Bristol-Myers Squibb Company Activatable anti-ctla-4 antibodies and uses thereof
US9975957B2 (en) 2014-03-31 2018-05-22 Genentech, Inc. Anti-OX40 antibodies and methods of use
WO2018093821A1 (en) 2016-11-15 2018-05-24 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
US9987500B2 (en) 2014-01-23 2018-06-05 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-1
US9988452B2 (en) 2014-10-14 2018-06-05 Novartis Ag Antibody molecules to PD-L1 and uses thereof
WO2018099978A1 (en) 2016-11-29 2018-06-07 Horst Lindhofer Combination of t-cell redirecting multifunctional antibodies with immune checkpoint modulators and uses thereof
WO2018110515A1 (en) 2016-12-12 2018-06-21 第一三共株式会社 Combination of antibody-drug conjugate and immune checkpoint inhibitor
WO2018111890A1 (en) 2016-12-12 2018-06-21 Genentech, Inc. Methods of treating cancer using anti-pd-l1 antibodies and antiandrogens
WO2018129497A1 (en) 2017-01-09 2018-07-12 Bioxcel Therapeutics, Inc. Predictive and diagnostic methods for prostate cancer
WO2018127570A1 (en) 2017-01-05 2018-07-12 Netris Pharma Combined treatment with netrin-1 interfering drug and immune checkpoint inhibitors drugs
EP3277320A4 (en) * 2015-03-30 2018-08-01 Stcube, Inc. Antibodies specific to glycosylated pd-l1 and methods of use thereof
WO2018138591A1 (en) 2017-01-24 2018-08-02 Pfizer Inc. Calicheamicin derivatives and antibody drug conjugates thereof
WO2018144999A1 (en) 2017-02-06 2018-08-09 Orionis Biosciences, Inc. Targeted engineered interferon and uses thereof
WO2018141964A1 (en) 2017-02-06 2018-08-09 Orionis Biosciences Nv Targeted chimeric proteins and uses thereof
WO2018141959A1 (en) 2017-02-06 2018-08-09 Innate Pharma Immunomodulatory antibody drug conjugates binding to a human mica polypeptide
WO2018150224A1 (en) 2017-02-16 2018-08-23 Shenzhen Runshin Bioscience Anti-programmed death-ligand 1 (pd-l1) antibodies and therapeutic uses thereof
WO2018152396A1 (en) 2017-02-17 2018-08-23 Innate Tumor Immunity, Inc. Substituted imidazo-quinolines as nlrp3 modulators
WO2018154520A1 (en) 2017-02-27 2018-08-30 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2018160841A1 (en) 2017-03-01 2018-09-07 Genentech, Inc. Diagnostic and therapeutic methods for cancer
US10072087B2 (en) 2009-12-10 2018-09-11 Hoffmann-La Roche Inc. Antibodies against human CSF-1R and uses thereof
US10076518B2 (en) 2015-03-06 2018-09-18 Beyondspring Pharmaceuticals, Inc. Method of treating a brain tumor
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
WO2018167267A1 (en) 2017-03-16 2018-09-20 Innate Pharma Compositions and methods for treating cancer
WO2018170168A1 (en) 2017-03-15 2018-09-20 Cue Biopharma, Inc. Methods for modulating an immune response
WO2018172508A1 (en) 2017-03-24 2018-09-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
WO2018183956A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Naphthyridines as inhibitors of hpk1
WO2018183964A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Isoquinolines as inhibitors of hpk1
EP3309177A4 (en) * 2016-03-04 2018-10-10 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Pdl-1 antibody, pharmaceutical composition thereof, and uses thereof
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018191660A1 (en) 2017-04-14 2018-10-18 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2018189220A1 (en) 2017-04-13 2018-10-18 F. Hoffmann-La Roche Ag An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer
WO2018194496A2 (en) 2017-04-17 2018-10-25 Закрытое Акционерное Общество "Биокад" Monoclonal antibody to pd-l1
WO2018200430A1 (en) 2017-04-26 2018-11-01 Bristol-Myers Squibb Company Methods of antibody production that minimize disulfide bond reduction
EP2926142B1 (en) 2012-11-30 2018-11-07 F.Hoffmann-La Roche Ag Identification of patients in need of pd-l1 inhibitor cotherapy
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
WO2018219956A1 (en) 2017-05-29 2018-12-06 Gamamabs Pharma Cancer-associated immunosuppression inhibitor
WO2018222718A1 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
WO2018223040A1 (en) 2017-06-01 2018-12-06 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-pd-1 antibody
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
WO2018220099A1 (en) 2017-06-02 2018-12-06 F. Hoffmann-La Roche Ag Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
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
US10155748B2 (en) 2015-07-13 2018-12-18 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
US10167336B2 (en) 2013-03-14 2019-01-01 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
WO2019011855A1 (en) 2017-07-10 2019-01-17 Innate Pharma Siglec-9-neutralizing antibodies
WO2019014402A1 (en) 2017-07-14 2019-01-17 Innate Tumor Immunity, Inc. Nlrp3 modulators
EP3360893A4 (en) * 2015-10-10 2019-01-23 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences High-affinity and soluble pdl-1 molecule
WO2019018757A1 (en) 2017-07-21 2019-01-24 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2019032431A1 (en) 2017-08-07 2019-02-14 Amgen Inc. Treatment of triple negative breast cancer or colorectal cancer with liver metastases with an anti pd-l1 antibody and an oncolytic virus
US10214586B2 (en) 2015-08-24 2019-02-26 Eli Lilly And Company PD-L1 antibodies
US10238650B2 (en) 2015-03-06 2019-03-26 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
WO2019059411A1 (en) 2017-09-20 2019-03-28 Chugai Seiyaku Kabushiki Kaisha Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent
EP3348571A4 (en) * 2015-07-31 2019-04-10 Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Single domain antibody for programmed death-ligand (pd-l1) and derived protein thereof
WO2019069269A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting) useful in treating hiv
WO2019068907A1 (en) 2017-10-06 2019-04-11 Innate Pharma Restoration of t cell activity via the cd39/cd73 axis
WO2019069270A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting)
US10259875B2 (en) 2013-10-01 2019-04-16 Mayo Foundation For Medical Education And Research Methods for treating cancer in patients with elevated levels of BIM
EP3470426A1 (en) 2017-10-10 2019-04-17 Numab Therapeutics AG Multispecific antibody
WO2019072871A2 (en) 2017-10-09 2019-04-18 Enterome S.A. Microbiota sequence variants of tumor-related antigenic epitopes
WO2019075090A1 (en) 2017-10-10 2019-04-18 Tilos Therapeutics, Inc. Anti-lap antibodies and uses thereof
WO2019072870A1 (en) 2017-10-10 2019-04-18 Numab Innovation Ag Antibodies targeting cd137 and methods of use thereof
WO2019072868A1 (en) 2017-10-10 2019-04-18 Numab Therapeutics AG Multispecific antibody
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company Methods of treating tumor
WO2019079520A2 (en) 2017-10-18 2019-04-25 Alpine Immune Sciences, Inc. Variant icos ligand immunomodulatory proteins and related compositions and methods
EP3292873B1 (en) 2013-02-22 2019-05-01 CureVac AG Combination of vaccination and inhibition of the pd-1 pathway
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2019089921A1 (en) 2017-11-01 2019-05-09 Bristol-Myers Squibb Company Immunostimulatory agonistic antibodies for use in treating cancer
WO2019090330A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Methods of treating a tumor
WO2019097369A1 (en) 2017-11-14 2019-05-23 Pfizer Inc. Ezh2 inhibitor combination therapies
US10302653B2 (en) 2014-05-22 2019-05-28 Mayo Foundation For Medical Education And Research Distinguishing antagonistic and agonistic anti B7-H1 antibodies
US10328158B2 (en) 2014-01-10 2019-06-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
WO2019122884A1 (en) 2017-12-19 2019-06-27 Kymab Limited Antibodies to icos
CN109963589A (en) * 2016-10-30 2019-07-02 上海复宏汉霖生物技术股份有限公司 Anti- PD-L1 antibody and variant
WO2019133747A1 (en) 2017-12-27 2019-07-04 Bristol-Myers Squibb Company Anti-cd40 antibodies and uses thereof
WO2019134946A1 (en) 2018-01-04 2019-07-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma resistant
WO2019140150A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2019144126A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
WO2019143607A1 (en) 2018-01-16 2019-07-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2019144098A1 (en) 2018-01-22 2019-07-25 Bristol-Myers Squibb Company Compositions and methods of treating cancer
EP3378871A4 (en) * 2015-11-17 2019-08-07 Suzhou Suncadia Biopharmaceuticals Co., Ltd. Pd-l1 antibody, antigen fragment binding thereof and pharmaceutical use thereof
WO2019157124A1 (en) 2018-02-08 2019-08-15 Bristol-Myers Squibb Company Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors
WO2019165434A1 (en) 2018-02-26 2019-08-29 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2019162325A1 (en) 2018-02-21 2019-08-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors
WO2019175113A1 (en) 2018-03-12 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
WO2019190327A2 (en) 2018-03-30 2019-10-03 Merus N.V. Multivalent antibody
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
EP3550019A1 (en) 2014-10-24 2019-10-09 Astrazeneca AB Combination
CN110337449A (en) * 2017-02-21 2019-10-15 上海君实生物医药科技股份有限公司 Anti- PD-L1 antibody and its application
WO2019200256A1 (en) 2018-04-12 2019-10-17 Bristol-Myers Squibb Company Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody
US10457725B2 (en) 2016-05-13 2019-10-29 Regeneron Pharmaceuticals, Inc. Methods of treating skin cancer by administering a PD-1 inhibitor
WO2019209896A1 (en) 2018-04-25 2019-10-31 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2019211489A1 (en) 2018-05-04 2019-11-07 Merck Patent Gmbh COMBINED INHIBITION OF PD-1/PD-L1, TGFβ AND DNA-PK FOR THE TREATMENT OF CANCER
WO2019211492A1 (en) 2018-05-04 2019-11-07 Tollys Tlr3 ligands that activate both epithelial and myeloid cells
WO2019219820A1 (en) 2018-05-16 2019-11-21 Ctxt Pty Limited Substituted condensed thiophenes as modulators of sting
WO2019229699A1 (en) 2018-05-31 2019-12-05 Novartis Ag Hepatitis b antibodies
WO2019241730A2 (en) 2018-06-15 2019-12-19 Flagship Pioneering Innovations V, Inc. Increasing immune activity through modulation of postcellular signaling factors
WO2019243252A1 (en) 2018-06-18 2019-12-26 Innate Pharma Compositions and methods for treating cancer
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
US10517875B2 (en) 2014-07-23 2019-12-31 Mayo Foundation for Medical Engineering and Research Targeting DNA-PKcs and B7-H1 to treat cancer
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
WO2020014583A1 (en) 2018-07-13 2020-01-16 Bristol-Myers Squibb Company Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a mehtod of treating a cancer or a solid tumor
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
WO2020011964A1 (en) 2018-07-12 2020-01-16 F-Star Beta Limited Antibody molecules that bind pd-l1 and cd137
WO2020018789A1 (en) 2018-07-18 2020-01-23 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
WO2020023707A1 (en) 2018-07-26 2020-01-30 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020023551A1 (en) 2018-07-24 2020-01-30 Genentech, Inc. Naphthyridine compounds and uses thereof
WO2020023560A1 (en) 2018-07-24 2020-01-30 F. Hoffmann-La Roche Ag Isoquinoline compounds and uses thereof
US10548988B2 (en) 2012-07-18 2020-02-04 Birdie Biopharmaceuticals, Inc. Compounds for targeted immunotherapy
WO2020037094A1 (en) 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Substitued 4-amino-1h-imidazo[4,5-c]quinoline compounds and improved methods for their preparation
WO2020037091A1 (en) 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Imidazo[4,5-c]quinoline derived nlrp3-modulators
WO2020037092A1 (en) 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Imidazo[4,5-c]quinoline derived nlrp3-modulators
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
EP2943507B1 (en) 2013-01-10 2020-02-26 Genmab A/S Inert format
WO2020043683A1 (en) 2018-08-27 2020-03-05 Pieris Pharmaceuticals Gmbh Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof
WO2020044206A1 (en) 2018-08-29 2020-03-05 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors for use in the treatment cancer
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020048942A1 (en) 2018-09-04 2020-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses
WO2020053742A2 (en) 2018-09-10 2020-03-19 Novartis Ag Anti-hla-hbv peptide antibodies
US10596257B2 (en) 2016-01-08 2020-03-24 Hoffmann-La Roche Inc. Methods of treating CEA-positive cancers using PD-1 axis binding antagonists and anti-CEA/anti-CD3 bispecific antibodies
WO2020061349A1 (en) 2018-09-21 2020-03-26 Genentech, Inc. Diagnostic methods for triple-negative breast cancer
WO2020061060A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2020058372A1 (en) 2018-09-19 2020-03-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy
WO2020061377A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
WO2020069402A1 (en) 2018-09-30 2020-04-02 Genentech, Inc. Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
WO2020072627A1 (en) 2018-10-02 2020-04-09 Genentech, Inc. Isoquinoline compounds for the treatment of cancer
WO2020072695A1 (en) 2018-10-03 2020-04-09 Genentech, Inc. 8-aminoisoquinoline compounds and uses thereof
WO2020070053A1 (en) 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of stress granule formation for targeting the regulation of immune responses
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
WO2020081767A1 (en) 2018-10-18 2020-04-23 Genentech, Inc. Diagnostic and therapeutic methods for sarcomatoid kidney cancer
WO2020081928A1 (en) 2018-10-19 2020-04-23 Bristol-Myers Squibb Company Combination therapy for melanoma
WO2020086724A1 (en) 2018-10-23 2020-04-30 Bristol-Myers Squibb Company Methods of treating tumor
WO2020092304A1 (en) 2018-10-29 2020-05-07 Wisconsin Alumni Research Foundation Dendritic polymers complexed with immune checkpoint inhibitors for enhanced cancer immunotherapy
US10646567B2 (en) 2011-08-01 2020-05-12 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
WO2020102728A1 (en) 2018-11-16 2020-05-22 Neoimmunetech, Inc. Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor
WO2020102804A2 (en) 2018-11-16 2020-05-22 Arqule, Inc. Pharmaceutical combination for treatment of cancer
US10662253B2 (en) 2008-01-31 2020-05-26 Inserm (Institut National De La Sante Et De La Recherche Medicale) Antibodies against human CD39 and use thereof for inhibiting T regulatory cells activity
WO2020104479A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies
WO2020104496A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Bispecific antibody targeting transferrin receptor 1 and soluble antigen
WO2020112781A1 (en) 2018-11-28 2020-06-04 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2020109570A1 (en) 2018-11-30 2020-06-04 Gbg Forschungs Gmbh Method for predicting the response to cancer immunotherapy in cancer patients
WO2020109355A1 (en) 2018-11-28 2020-06-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and kit for assaying lytic potential of immune effector cells
WO2020115261A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2020117952A2 (en) 2018-12-05 2020-06-11 Genentech, Inc. Diagnostic methods and compositions for cancer immunotherapy
WO2020117849A1 (en) 2018-12-04 2020-06-11 Bristol-Myers Squibb Company Methods of analysis using in-sample calibration curve by multiple isotopologue reaction monitoring
WO2020115262A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of cd26 and cd39 as new phenotypic markers for assessing maturation of foxp3+ t cells and uses thereof for diagnostic purposes
EP3433277A4 (en) * 2016-03-23 2020-06-17 Mabspace Biosciences (Suzhou) Co., Ltd Novel anti-pd-l1 antibodies
WO2020120592A1 (en) 2018-12-12 2020-06-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating melanoma
WO2020127885A1 (en) 2018-12-21 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions for treating cancers and resistant cancers
WO2020132560A2 (en) 2018-12-21 2020-06-25 Aim Immunotech Inc. Compositions and methods for cancer therapy
WO2020127411A1 (en) 2018-12-19 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d
WO2020132297A1 (en) 2018-12-19 2020-06-25 Cue Biopharma, Inc. Multimeric t-cell modulatory polypeptides and methods of use thereof
WO2020127059A1 (en) 2018-12-17 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sulconazole as a furin inhibitor
WO2020136235A1 (en) 2018-12-28 2020-07-02 Transgene Sa M2-defective poxvirus
WO2020136147A1 (en) 2018-12-26 2020-07-02 Innate Pharma Compounds and methods for treatment of head and neck cancer
WO2020150115A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2020150116A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2020148338A1 (en) 2019-01-15 2020-07-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy
WO2020150114A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Heterocyclic nlrp3 modulators, for use in the treatment of cancer
WO2020150152A1 (en) 2019-01-14 2020-07-23 Genentech, Inc. Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine
WO2020150113A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Substituted quinazolines as nlrp3 modulators, for use in the treatment of cancer
EP3478723A4 (en) * 2016-06-29 2020-07-29 Checkpoint Therapeutics, Inc. Pd-l1-specific antibodies and methods of using the same
EP3689910A2 (en) 2014-09-23 2020-08-05 F. Hoffmann-La Roche AG Method of using anti-cd79b immunoconjugates
WO2020157131A1 (en) 2019-01-30 2020-08-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor
WO2020161083A1 (en) 2019-02-04 2020-08-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating blood-brain barrier
WO2020163589A1 (en) 2019-02-08 2020-08-13 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2020165370A1 (en) 2019-02-13 2020-08-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for selecting a cancer treatment in a subject suffering from cancer
WO2020169472A2 (en) 2019-02-18 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of inducing phenotypic changes in macrophages
WO2020186176A1 (en) 2019-03-14 2020-09-17 Genentech, Inc. Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab
WO2020198672A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020198676A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020201568A1 (en) 2019-04-03 2020-10-08 Targimmune Therapeutics Ag Immunotherapy for the treatment of cancer
WO2020201362A2 (en) 2019-04-02 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
WO2020205626A1 (en) 2019-03-29 2020-10-08 Genentech, Inc. Modulators of cell surface protein interactions and methods and compositions related to same
WO2020208060A1 (en) 2019-04-09 2020-10-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk2 inhibitors in combination with immune checkpoint blockade therapy for the treatment of cancer
WO2020214995A1 (en) 2019-04-19 2020-10-22 Genentech, Inc. Anti-mertk antibodies and their methods of use
WO2020212484A1 (en) 2019-04-17 2020-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treatment of nlrp3 inflammasome mediated il-1beta dependent disorders
WO2020216697A1 (en) 2019-04-23 2020-10-29 Innate Pharma Cd73 blocking antibodies
WO2020221796A1 (en) 2019-04-30 2020-11-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
EP3736294A2 (en) 2014-10-10 2020-11-11 Innate Pharma Cd73 blockade
WO2020226986A2 (en) 2019-05-03 2020-11-12 Genentech, Inc. Methods of treating cancer with an anti-pd-l1 antibody
WO2020227159A2 (en) 2019-05-03 2020-11-12 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity
WO2020232375A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Oxoacridinyl acetic acid derivatives and methods of use
WO2020232378A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use
WO2020234875A2 (en) 2019-05-19 2020-11-26 Yeda Research And Development Co. Ltd. Identification of recurrent mutated neopeptides
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
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2020239558A1 (en) 2019-05-24 2020-12-03 Pfizer Inc. Combination therapies using cdk inhibitors
US10858432B2 (en) 2015-12-02 2020-12-08 Stcube, Inc. Antibodies specific to glycosylated PD-1 and methods of use thereof
CN112105644A (en) * 2018-03-23 2020-12-18 得克萨斯州大学系统董事会 Dual specific antibodies to human PD-L1 and PD-L2 and methods of use thereof
EP3763742A1 (en) 2014-09-01 2021-01-13 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
WO2021009365A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting
WO2021009362A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting
WO2021009267A1 (en) 2019-07-15 2021-01-21 Capella Bioscience Ltd Anti-pd-l1 antibodies
WO2021019526A1 (en) 2019-07-29 2021-02-04 Yeda Research And Development Co. Ltd. Methods of treating and diagnosing lung cancer
US10912748B2 (en) 2016-02-08 2021-02-09 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
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
US10927158B2 (en) 2016-12-22 2021-02-23 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
EP3783029A1 (en) 2015-05-12 2021-02-24 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
EP3789402A1 (en) 2014-11-20 2021-03-10 F. Hoffmann-La Roche AG Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists
EP3789399A1 (en) 2014-11-21 2021-03-10 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2021048292A1 (en) 2019-09-11 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
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
WO2021062018A1 (en) 2019-09-25 2021-04-01 Bristol-Myers Squibb Company Composite biomarker for cancer therapy
WO2021062085A1 (en) 2019-09-27 2021-04-01 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
EP3799885A1 (en) 2014-09-16 2021-04-07 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
EP3626266A4 (en) * 2017-05-16 2021-04-07 Jiangsu Hengrui Medicine Co., Ltd. Pd-l1 antibody pharmaceutical composition and use thereof
EP3800201A1 (en) 2019-10-01 2021-04-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Cd28h stimulation enhances nk cell killing activities
WO2021064180A1 (en) 2019-10-03 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating macrophages polarization
WO2021064184A1 (en) 2019-10-04 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer
WO2021064567A1 (en) 2019-09-30 2021-04-08 Astrazeneca Ab Combination treatment for cancer
EP3804620A1 (en) 2016-03-01 2021-04-14 North Carolina State University Enhanced cancer immunotherapy by microneedle patch-assisted delivery
WO2021074391A1 (en) 2019-10-17 2021-04-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing nasal intestinal type adenocarcinomas
WO2021079958A1 (en) 2019-10-25 2021-04-29 第一三共株式会社 Combination of anti-garp antibody and immunoregulator
WO2021083959A1 (en) 2019-10-29 2021-05-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating uveal melanoma
CN112805297A (en) * 2018-07-14 2021-05-14 财团法人生物技术开发中心 Anti-human PD-L1 antibodies and uses thereof
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
WO2021090146A1 (en) 2019-11-04 2021-05-14 Astrazeneca Ab Combination therapy for treating cancer
WO2021092171A1 (en) 2019-11-06 2021-05-14 Genentech, Inc. Diagnostic and therapeutic methods for treatment of hematologic cancers
WO2021091964A1 (en) 2019-11-04 2021-05-14 Duke University Treatment for primary and metastatic cancer
WO2021092380A1 (en) 2019-11-08 2021-05-14 Bristol-Myers Squibb Company Lag-3 antagonist therapy for melanoma
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
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
WO2021106978A1 (en) 2019-11-27 2021-06-03 サイトリミック株式会社 Pharmaceutical composition
US11040948B2 (en) 2017-09-29 2021-06-22 Curis, Inc. Crystal forms of immunomodulators
WO2021123243A1 (en) 2019-12-19 2021-06-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and vaccine compositions to treat cancers
WO2021127217A1 (en) 2019-12-17 2021-06-24 Flagship Pioneering Innovations V, Inc. Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly
WO2021127554A1 (en) 2019-12-19 2021-06-24 Bristol-Myers Squibb Company Combinations of dgk inhibitors and checkpoint antagonists
US11046781B2 (en) 2016-01-07 2021-06-29 Birdie Biopharmaceuticals, Inc. Anti-HER2 combinations for treating tumors
US11053240B2 (en) 2017-04-27 2021-07-06 Birdie Biopharmaceuticals, Inc. 2-amino-quinoline derivatives
WO2021142203A1 (en) 2020-01-10 2021-07-15 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2021144426A1 (en) 2020-01-17 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2021155149A1 (en) 2020-01-31 2021-08-05 Genentech, Inc. Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine
WO2021154073A1 (en) 2020-01-29 2021-08-05 Merus N.V. Means and method for modulating immune cell engaging effects.
WO2021152548A1 (en) 2020-01-30 2021-08-05 Benitah Salvador Aznar Combination therapy for treatment of cancer and cancer metastasis
WO2021156360A1 (en) 2020-02-05 2021-08-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki)
WO2021158938A1 (en) 2020-02-06 2021-08-12 Bristol-Myers Squibb Company Il-10 and uses thereof
WO2021158635A1 (en) 2020-02-07 2021-08-12 Al Therapeutics, Inc. Anti-viral compositions and methods of use
WO2021174045A1 (en) 2020-02-28 2021-09-02 Bristol-Myers Squibb Company Radiolabeled fibronectin based scaffolds and antibodies and theranostic uses thereof
WO2021170777A1 (en) 2020-02-28 2021-09-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing, prognosing and managing treatment of breast cancer
US11110168B2 (en) 2016-03-15 2021-09-07 North Carolina State University Nanoparticles, controlled-release dosage forms, and methods for delivering an immunotherapeutic agent
US11110157B2 (en) 2014-03-12 2021-09-07 Curevac Ag Combination of vaccination and OX40 agonists
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
WO2021176424A1 (en) 2020-03-06 2021-09-10 Ona Therapeutics, S.L. Anti-cd36 antibodies and their use to treat cancer
WO2021178807A1 (en) 2020-03-06 2021-09-10 Celgene Quanticel Research, Inc. Combination of an lsd-1 inhibitor and nivolumab for use in treating sclc or sqnsclc
EP3878446A1 (en) 2020-03-09 2021-09-15 Universite De Geneve Hsd11b1 inhibitors for use in immunotherapy and uses thereof
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021195485A1 (en) * 2020-03-27 2021-09-30 Vanderbilt University Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (sars-cov-2)
US11136300B2 (en) 2017-10-11 2021-10-05 Aurigene Discovery Technologies Limited Crystalline forms of 3-substituted 1,2,4-oxadiazole
US11136397B2 (en) 2016-01-07 2021-10-05 Birdie Pharmaceuticals, Inc. Anti-EGFR combinations for treating tumors
WO2021202959A1 (en) 2020-04-03 2021-10-07 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2021207449A1 (en) 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
WO2021205444A1 (en) 2020-04-06 2021-10-14 Yeda Research And Development Co. Ltd. Methods of diagnosing cancer and predicting responsiveness to therapy
WO2021222167A1 (en) 2020-04-28 2021-11-04 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
WO2021224215A1 (en) 2020-05-05 2021-11-11 F. Hoffmann-La Roche Ag Predicting response to pd-1 axis inhibitors
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
WO2021239838A2 (en) 2020-05-26 2021-12-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes
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
WO2021252977A1 (en) 2020-06-12 2021-12-16 Genentech, Inc. Methods and compositions for cancer immunotherapy
WO2021249969A1 (en) 2020-06-10 2021-12-16 Merck Patent Gmbh Combination product for the treatment of cancer diseases
WO2021257503A1 (en) 2020-06-16 2021-12-23 Genentech, Inc. Methods and compositions for treating triple-negative breast cancer
WO2021257124A1 (en) 2020-06-18 2021-12-23 Genentech, Inc. Treatment with anti-tigit antibodies and pd-1 axis binding antagonists
US11214619B2 (en) 2018-07-20 2022-01-04 Surface Oncology, Inc. Anti-CD112R compositions and methods
WO2022006179A1 (en) 2020-06-29 2022-01-06 Flagship Pioneering Innovations V, Inc. Viruses engineered to promote thanotransmission and their use in treating cancer
US11220552B2 (en) 2016-01-07 2022-01-11 Birdie Biopharmaceuticals, Inc. Anti-CD20 combinations for treating tumors
WO2022008519A1 (en) 2020-07-07 2022-01-13 BioNTech SE Therapeutic rna for hpv-positive cancer
US11229642B2 (en) 2016-06-06 2022-01-25 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing neutropenia
WO2022020716A1 (en) 2020-07-24 2022-01-27 Genentech, Inc. Heterocyclic inhibitors of tead for treating cancer
WO2022023379A1 (en) 2020-07-28 2022-02-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for preventing and treating a cancer
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
WO2022036146A1 (en) 2020-08-12 2022-02-17 Genentech, Inc. Diagnostic and therapeutic methods for cancer
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
EA039736B1 (en) * 2015-09-15 2022-03-04 Сайтомкс Терапьютикс, Инк. Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof
WO2022050954A1 (en) 2020-09-04 2022-03-10 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2022053703A1 (en) 2020-09-14 2022-03-17 Boehringer Ingelheim International Gmbh Heterologous prime boost vaccine
US11287428B2 (en) 2016-03-16 2022-03-29 H. Lee Moffitt Cancer Center And Research Institute, Inc. PD1 and PDL-1 expression during progression from myelodysplastic syndrome to acute myelogenous leukemia
US11291718B2 (en) 2016-10-11 2022-04-05 Cytlimic Inc. Method for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein
US11292842B2 (en) 2017-02-21 2022-04-05 Regeneron Pharmaceuticals, Inc. Anti-PD-1 antibodies for treatment of lung cancer
US11299544B2 (en) 2013-03-15 2022-04-12 Genentech, Inc. Biomarkers and methods of treating PD-1 and PD-L1 related conditions
WO2022076596A1 (en) 2020-10-06 2022-04-14 Codiak Biosciences, Inc. Extracellular vesicle-aso constructs targeting stat6
WO2022074152A1 (en) 2020-10-08 2022-04-14 Targimmune Therapeutics Ag Immunotherapy for the treatment of cancer
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022084210A1 (en) 2020-10-20 2022-04-28 F. Hoffmann-La Roche Ag Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors
WO2022084531A1 (en) 2020-10-23 2022-04-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating glioma
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
WO2022094567A1 (en) 2020-10-28 2022-05-05 Ikena Oncology, Inc. Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine
US11326170B2 (en) 2017-04-18 2022-05-10 Changchun Huapu Biotechnology Co. Ltd. Immunomodulatory polynucleotides and uses thereof
WO2022103904A1 (en) 2020-11-13 2022-05-19 Genentech, Inc. Methods and compositions comprising a krasg12c inhibitor and a pd-l1 binding antagonist for treating lung cancer
WO2022101463A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death
WO2022101484A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
WO2022101302A1 (en) 2020-11-12 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes
WO2022101481A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
US11339201B2 (en) 2016-05-18 2022-05-24 Albert Einstein College Of Medicine Variant PD-L1 polypeptides, T-cell modulatory multimeric polypeptides, and methods of use thereof
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies
WO2022119830A1 (en) 2020-12-02 2022-06-09 Genentech, Inc. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
EP3929215A4 (en) * 2019-06-10 2022-06-22 Shandong Boan Biotechnology Co., Ltd. Bifunctional fusion protein against pdl1 and tgf? and use thereof
US11370819B2 (en) 2014-02-10 2022-06-28 Merck Patent Gmbh Targeted TGFβ inhibition
WO2022136266A1 (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
WO2022136255A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
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
EP4026848A1 (en) 2015-12-09 2022-07-13 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing the cytokine release syndrome
WO2022148736A1 (en) 2021-01-05 2022-07-14 Transgene Vectorization of muc1 t cell engager
US11400086B2 (en) 2017-02-01 2022-08-02 Beyondspring Pharmaceuticals, Inc. Method of reducing chemotherapy-induced neutropenia
EP3841126A4 (en) * 2018-08-20 2022-08-10 1Globe Biomedical Co., Ltd. Novel cancer immunotherapy antibody compositions
WO2022183018A1 (en) * 2021-02-26 2022-09-01 Fred Hutchinson Cancer Research Center Protective antibodies against respiratory viral infections
US11440960B2 (en) 2017-06-20 2022-09-13 Kymab Limited TIGIT antibodies, encoding nucleic acids and methods of using said antibodies in vivo
WO2022194908A1 (en) 2021-03-17 2022-09-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2022203090A1 (en) 2021-03-25 2022-09-29 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 for treatment of cancer
US11458195B2 (en) 2013-02-22 2022-10-04 Curevac Ag Combination of vaccination and inhibition of the PD-1 pathway
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022212784A1 (en) 2021-03-31 2022-10-06 Flagship Pioneering Innovations V, Inc. Thanotransmission polypeptides and their use in treating cancer
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
WO2022216898A1 (en) 2021-04-09 2022-10-13 Genentech, Inc. Combination therapy with a raf inhibitor and a pd-1 axis inhibitor
WO2022217123A2 (en) 2021-04-08 2022-10-13 Nurix Therapeutics, Inc. Combination therapies with cbl-b inhibitor compounds
WO2022219080A1 (en) 2021-04-14 2022-10-20 INSERM (Institut National de la Santé et de la Recherche Médicale) New method to improve nk cells cytotoxicity
WO2022223791A1 (en) 2021-04-23 2022-10-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cell senescence accumulation related disease
WO2022229966A1 (en) 2021-04-29 2022-11-03 Yeda Research And Development Co. Ltd. T cell receptors directed against ras-derived recurrent neoantigens and methods of identifying same
WO2022232503A1 (en) 2021-04-30 2022-11-03 Genentech, Inc. Therapeutic and diagnostic methods and compositions for cancer
US11491204B2 (en) 2015-04-07 2022-11-08 Cytlimic Inc. Composition comprising poly I:C and LAG-3-IGG fusion protein
US11492383B2 (en) 2011-06-24 2022-11-08 Stephen D. Gillies Light chain immunoglobulin fusion proteins and methods of use thereof
US11498968B2 (en) 2016-12-22 2022-11-15 Hoffmann-La Roche Inc. Treatment of tumors with an anti-CSF-1R antibody in combination with an anti-PD-L1 antibody after failure of anti-PD-L1/PD1 treatment
US11497734B2 (en) 2017-11-03 2022-11-15 Aurigene Discovery Technologies Limited Dual inhibitors of TIM-3 and PD-1 pathways
US11497735B2 (en) 2017-11-06 2022-11-15 Aurigene Discovery Technologies Limited Conjoint therapies for immunomodulation
US11505591B2 (en) 2016-05-18 2022-11-22 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
WO2022243378A1 (en) 2021-05-18 2022-11-24 Kymab Limited Uses of anti-icos antibodies
US11517567B2 (en) 2017-06-23 2022-12-06 Birdie Biopharmaceuticals, Inc. Pharmaceutical compositions
WO2022254227A1 (en) 2021-06-04 2022-12-08 Kymab Limited Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies
US11525002B2 (en) 2017-10-11 2022-12-13 Board Of Regents, The University Of Texas System Human PD-L1 antibodies and methods of use therefor
EP3902563A4 (en) * 2018-12-27 2022-12-28 Gigagen, Inc. Anti-pd-l1 binding proteins and methods of use thereof
US11542335B2 (en) 2016-08-25 2023-01-03 Hoffmann-La Roche Inc. Method of treating cancer in a patient by administering an antibody which binds colony stimulating factor-1 receptor (CSF-1R)
WO2023278641A1 (en) 2021-06-29 2023-01-05 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
WO2023279092A2 (en) 2021-07-02 2023-01-05 Genentech, Inc. Methods and compositions for treating cancer
WO2023280790A1 (en) 2021-07-05 2023-01-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Gene signatures for predicting survival time in patients suffering from renal cell carcinoma
WO2023285552A1 (en) 2021-07-13 2023-01-19 BioNTech SE Multispecific binding agents against cd40 and cd137 in combination therapy for cancer
US11560425B2 (en) 2017-06-27 2023-01-24 Neuracle Science Co., Ltd. Use of anti-FAM19A5 antibodies for treating cancers
US11564995B2 (en) 2018-10-29 2023-01-31 Wisconsin Alumni Research Foundation Peptide-nanoparticle conjugates
WO2023007472A1 (en) 2021-07-30 2023-02-02 ONA Therapeutics S.L. Anti-cd36 antibodies and their use to treat cancer
WO2023010094A2 (en) 2021-07-28 2023-02-02 Genentech, Inc. Methods and compositions for treating cancer
WO2023010095A1 (en) 2021-07-28 2023-02-02 F. Hoffmann-La Roche Ag Methods and compositions for treating cancer
US11578372B2 (en) 2012-11-05 2023-02-14 Foundation Medicine, Inc. NTRK1 fusion molecules and uses thereof
EP3929213A4 (en) * 2019-02-21 2023-03-08 Eucure (Beijing) Biopharma Co., Ltd Anti-pd-l1 antibody and use thereof
US11603407B2 (en) 2017-04-06 2023-03-14 Regeneron Pharmaceuticals, Inc. Stable antibody formulation
WO2023056403A1 (en) 2021-09-30 2023-04-06 Genentech, Inc. Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists
WO2023052531A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
WO2023057882A1 (en) 2021-10-05 2023-04-13 Pfizer Inc. Combinations of azalactam compounds with a pd-1 axis binding antagonist for the treatment of cancer
US11629189B2 (en) 2017-12-19 2023-04-18 Kymab Limited Bispecific antibody for ICOS and PD-L1
WO2023061930A1 (en) 2021-10-11 2023-04-20 BioNTech SE Therapeutic rna for lung cancer
US11633393B2 (en) 2017-01-06 2023-04-25 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
WO2023077034A1 (en) 2021-10-28 2023-05-04 Lyell Immunopharma, Inc. Methods for culturing immune cells
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
WO2023078900A1 (en) 2021-11-03 2023-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating triple negative breast cancer (tnbc)
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
WO2023079428A1 (en) 2021-11-03 2023-05-11 Pfizer Inc. Combination therapies using tlr7/8 agonist
WO2023083868A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
WO2023088968A1 (en) 2021-11-17 2023-05-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Universal sarbecovirus vaccines
US11660352B2 (en) 2016-03-29 2023-05-30 Stcube, Inc. Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
WO2023118165A1 (en) 2021-12-21 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2023129438A1 (en) 2021-12-28 2023-07-06 Wisconsin Alumni Research Foundation Hydrogel compositions for use for depletion of tumor associated macrophages
US11702461B2 (en) 2018-01-09 2023-07-18 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides comprising reduced-affinity immunomodulatory polypeptides
WO2023137161A1 (en) 2022-01-14 2023-07-20 Amgen Inc. Triple blockade of tigit, cd112r, and pd-l1
WO2023147371A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
US11732044B2 (en) 2017-12-27 2023-08-22 Innovent Biologics (Suzhou) Co., Ltd. Anti-LAG-3 antibody and use thereof
WO2023164638A1 (en) 2022-02-25 2023-08-31 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma
US11746152B2 (en) 2016-07-20 2023-09-05 Stcube, Inc. Methods of cancer treatment and therapy using a combination of antibodies that bind glycosylated PD-L1
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
US11753479B2 (en) 2014-03-04 2023-09-12 Kymab Limited Nucleic acids encoding anti-OX40L antibodies
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
EP4249066A2 (en) 2014-12-23 2023-09-27 Bristol-Myers Squibb Company Antibodies to tigit
US11771698B2 (en) 2013-01-18 2023-10-03 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023192478A1 (en) 2022-04-01 2023-10-05 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
US11779604B2 (en) 2016-11-03 2023-10-10 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses and methods
WO2023196987A1 (en) 2022-04-07 2023-10-12 Bristol-Myers Squibb Company Methods of treating tumor
WO2023196964A1 (en) 2022-04-08 2023-10-12 Bristol-Myers Squibb Company Machine learning identification, classification, and quantification of tertiary lymphoid structures
US11786523B2 (en) 2018-01-24 2023-10-17 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing thrombocytopenia
WO2023201291A1 (en) 2022-04-13 2023-10-19 Genentech, Inc. Pharmaceutical compositions of mosunetuzumab and methods of use
WO2023201299A1 (en) 2022-04-13 2023-10-19 Genentech, Inc. Pharmaceutical compositions of therapeutic proteins and methods of use
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023220703A1 (en) 2022-05-12 2023-11-16 Genentech, Inc. Methods and compositions comprising a shp2 inhibitor and a pd-l1 binding antagonist
WO2023222854A1 (en) 2022-05-18 2023-11-23 Kymab Limited Uses of anti-icos antibodies
WO2023228095A1 (en) 2022-05-24 2023-11-30 Daiichi Sankyo Company, Limited Dosage regimen of an anti-cdh6 antibody-drug conjugate
WO2023235415A1 (en) 2022-06-01 2023-12-07 Genentech, Inc. Method to identify a patient with an increased likelihood of chemotherapy-induced peripheral neuropathy
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
US11840567B2 (en) 2017-10-03 2023-12-12 Joint Stock Company “Biocad” Bispecific antibodies with specific binding to CD47 and PD-L1
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
US11851471B2 (en) 2017-01-09 2023-12-26 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11858996B2 (en) 2016-08-09 2024-01-02 Kymab Limited Anti-ICOS antibodies
WO2024015897A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
US11878062B2 (en) 2020-05-12 2024-01-23 Cue Biopharma, Inc. Multimeric T-cell modulatory polypeptides and methods of use thereof
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024023750A1 (en) 2022-07-28 2024-02-01 Astrazeneca Uk Limited Combination of antibody-drug conjugate and bispecific checkpoint inhibitor
WO2024023740A1 (en) 2022-07-27 2024-02-01 Astrazeneca Ab Combinations of recombinant virus expressing interleukin-12 with pd-1/pd-l1 inhibitors
US11896643B2 (en) 2018-02-05 2024-02-13 Orionis Biosciences, Inc. Fibroblast binding agents and use thereof
WO2024033400A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sk2 inhibitor for the treatment of pancreatic cancer
WO2024033399A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sigmar1 ligand for the treatment of pancreatic cancer
WO2024049949A1 (en) 2022-09-01 2024-03-07 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2024054992A1 (en) 2022-09-09 2024-03-14 Bristol-Myers Squibb Company Methods of separating chelator
WO2024052356A1 (en) 2022-09-06 2024-03-14 Institut National de la Santé et de la Recherche Médicale Inhibitors of the ceramide metabolic pathway for overcoming immunotherapy resistance in cancer
US11933786B2 (en) 2015-03-30 2024-03-19 Stcube, Inc. Antibodies specific to glycosylated PD-L1 and methods of use thereof
WO2024056716A1 (en) 2022-09-14 2024-03-21 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy
WO2024069009A1 (en) 2022-09-30 2024-04-04 Alentis Therapeutics Ag Treatment of drug-resistant hepatocellular carcinoma
WO2024077095A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
WO2024077191A1 (en) 2022-10-05 2024-04-11 Flagship Pioneering Innovations V, Inc. Nucleic acid molecules encoding trif and additionalpolypeptides and their use in treating cancer
WO2024077166A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
RU2817281C2 (en) * 2014-09-11 2024-04-12 Медиммьюн Лимитед Antibodies to b7-h1 for treating tumours
WO2024084034A1 (en) 2022-10-21 2024-04-25 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of osteoarthritis
WO2024089417A1 (en) 2022-10-24 2024-05-02 Memorial Sloan-Kettering Cancer Center Tumour stratification for responsiveness to an immune checkpoint inhibitor
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
WO2024089418A1 (en) 2022-10-24 2024-05-02 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier
US11976128B2 (en) 2018-03-23 2024-05-07 Board Of Regents, The University Of Texas System Human PD-L2 antibodies and methods of use therefor
WO2024094688A1 (en) 2022-11-01 2024-05-10 Heidelberg Pharma Research Gmbh Anti-gucy2c antibody and uses thereof
EP4378957A2 (en) 2015-07-29 2024-06-05 Novartis AG Combination therapies comprising antibody molecules to pd-1
WO2024115725A1 (en) 2022-12-01 2024-06-06 BioNTech SE Multispecific antibody against cd40 and cd137 in combination therapy with anti-pd1 ab and chemotherapy
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
US12018065B2 (en) 2020-04-27 2024-06-25 Twist Bioscience Corporation Variant nucleic acid libraries for coronavirus
WO2024137776A1 (en) 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Combination therapy for lung cancer
WO2024137589A2 (en) 2022-12-20 2024-06-27 Genentech, Inc. Methods of treating pancreatic cancer with a pd-1 axis binding antagonist and an rna vaccine
US12029782B2 (en) 2020-09-09 2024-07-09 Cue Biopharma, Inc. MHC class II T-cell modulatory multimeric polypeptides for treating type 1 diabetes mellitus (T1D) and methods of use thereof
WO2024150017A1 (en) 2023-01-13 2024-07-18 Akrivia Biomedics Limited Method of profiling diseases
WO2024151687A1 (en) 2023-01-09 2024-07-18 Flagship Pioneering Innovations V, Inc. Genetic switches and their use in treating cancer
WO2024150177A1 (en) 2023-01-11 2024-07-18 Advesya Treatment methods for solid tumors
US12054557B2 (en) 2015-12-22 2024-08-06 Regeneron Pharmaceuticals, Inc. Combination of anti-PD-1 antibodies and bispecific anti-CD20/anti-CD3 antibodies to treat cancer
WO2024160721A1 (en) 2023-01-30 2024-08-08 Kymab Limited Antibodies
US12059474B2 (en) 2016-03-29 2024-08-13 Stcube & Co., Inc. Methods for selecting antibodies that specifically bind glycosylated immune checkpoint proteins
US12077588B2 (en) 2017-10-10 2024-09-03 Numab Therapeutics AG Antibodies targeting PDL1 and methods of use thereof
US12090142B2 (en) 2018-02-22 2024-09-17 Board Of Regents, The University Of Texas System Combination therapy for the treatment of cancer
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy
WO2024200571A1 (en) 2023-03-28 2024-10-03 Institut National de la Santé et de la Recherche Médicale Method for discriminating mono-immunotherapy from combined immunotherapy in cancers

Families Citing this family (278)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108997498A (en) 2008-12-09 2018-12-14 霍夫曼-拉罗奇有限公司 Anti- PD-L1 antibody and they be used to enhance the purposes of T cell function
DK3279215T3 (en) 2009-11-24 2020-04-27 Medimmune Ltd TARGETED BINDING AGENTS B7-H1
WO2013013188A1 (en) 2011-07-21 2013-01-24 Tolero Pharmaceuticals, Inc. Heterocyclic protein kinase inhibitors
MX362247B (en) 2013-03-06 2019-01-09 Astrazeneca Ab Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor.
WO2014165082A2 (en) * 2013-03-13 2014-10-09 Medimmune, Llc Antibodies and methods of detection
US20150071910A1 (en) * 2013-03-15 2015-03-12 Genentech, Inc. Biomarkers and methods of treating pd-1 and pd-l1 related conditions
WO2014169078A2 (en) 2013-04-09 2014-10-16 Boston Biomedical, Inc. Methods for treating cancer
AP2016009088A0 (en) 2013-09-16 2016-03-31 Astrazeneca Ab Therapeutic polymeric nanoparticles and methods of making and using same
US10202454B2 (en) * 2013-10-25 2019-02-12 Dana-Farber Cancer Institute, Inc. Anti-PD-L1 monoclonal antibodies and fragments thereof
AU2015203904B2 (en) * 2014-01-06 2018-07-19 Expression Pathology, Inc. SRM assay for PD-L1
EP3107538B1 (en) * 2014-02-18 2020-05-27 Health Research, Inc. Combination therapy for hepatocellular carcinoma
RU2702332C2 (en) 2014-05-13 2019-10-08 Медиммьюн Лимитед Antibodies to b7-h1 and to ctla-4 for treating non-small-cell lung cancer
KR20230144099A (en) 2014-05-15 2023-10-13 브리스톨-마이어스 스큅 컴퍼니 Treatment of lung cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent
AU2015265870B2 (en) 2014-05-29 2020-07-09 Ventana Medical Systems, Inc. PD-L1 antibodies and uses thereof
TW201618775A (en) 2014-08-11 2016-06-01 艾森塔製藥公司 Therapeutic combinations of a BTK inhibitor, a PI3K inhibitor, a JAK-2 inhibitor, a PD-1 inhibitor and/or a PD-L1 inhibitor
ES2727137T3 (en) 2014-08-28 2019-10-14 Halozyme Inc Therapy combined with a hyaluronan degradation enzyme and an immune control point inhibitor
CA3203273A1 (en) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same
SG11201703332SA (en) 2014-11-10 2017-05-30 Medimmune Ltd Binding molecules specific for cd73 and uses thereof
MA41414A (en) 2015-01-28 2017-12-05 Centre Nat Rech Scient ICOS AGONIST BINDING PROTEINS
MA41460A (en) 2015-02-03 2017-12-12 Oncomed Pharm Inc TNFRSF LIAISON AGENTS AND THEIR USES
EP3254110B1 (en) 2015-02-03 2020-03-18 Ventana Medical Systems, Inc. Histochemical assay for evaluating expression of programmed death ligand 1 (pd-l1)
WO2016128912A1 (en) 2015-02-12 2016-08-18 Acerta Pharma B.V. Therapeutic combinations of a btk inhibitor, a pi3k inhibitor, a jak-2 inhibitor, a pd-1 inhibitor, and/or a pd-l1 inhibitor
AU2016222928B2 (en) 2015-02-26 2021-05-13 Merck Patent Gmbh PD-1 / PD-L1 inhibitors for the treatment of cancer
WO2016150899A2 (en) 2015-03-23 2016-09-29 Bayer Pharma Aktiengesellschaft Anti-ceacam6 antibodies and uses thereof
US20180155429A1 (en) 2015-05-28 2018-06-07 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
US20160347848A1 (en) 2015-05-28 2016-12-01 Medimmune Limited Therapeutic combinations and methods for treating neoplasia
MA53355A (en) 2015-05-29 2022-03-16 Agenus Inc ANTI-CTLA-4 ANTIBODIES AND METHODS OF USE THEREOF
US11078278B2 (en) 2015-05-29 2021-08-03 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
EA201792623A1 (en) 2015-06-03 2018-04-30 Бостон Биомедикал, Инк. COMPOSITIONS CONTAINING CANCER STEM BONE INHIBITOR AND IMMUNOTHERAPEUTIC AGENT TO BE USED IN CANCER TREATMENT
WO2016197367A1 (en) 2015-06-11 2016-12-15 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
MY193229A (en) 2015-06-16 2022-09-26 Merck Patent Gmbh Pd-l1 antagonist combination treatments
FI3313441T3 (en) 2015-06-24 2024-03-28 Janssen Biotech Inc Immune modulation and treatment of solid tumors with antibodies that specifically bind cd38
EP3858859A1 (en) 2015-07-14 2021-08-04 Bristol-Myers Squibb Company Method of treating cancer using immune checkpoint inhibitor; antibody that binds to programmed death-1 receptor (pd-1) or programmed death ligand 1 (pd-l1)
CN108136025B (en) 2015-07-16 2022-09-06 比奥克斯塞尔医疗股份有限公司 A novel method of treating cancer using immunomodulation
US20180230431A1 (en) 2015-08-07 2018-08-16 Glaxosmithkline Intellectual Property Development Limited Combination Therapy
MA44909A (en) 2015-09-15 2018-07-25 Acerta Pharma Bv THERAPEUTIC ASSOCIATION OF A CD19 INHIBITOR AND A BTK INHIBITOR
SG11201803520PA (en) 2015-11-03 2018-05-30 Janssen Biotech Inc Antibodies specifically binding pd-1 and their uses
TWI795347B (en) 2015-11-18 2023-03-11 美商必治妥施貴寶公司 Treatment of lung cancer using a combination of an anti-pd-1 antibody and an anti-ctla-4 antibody
EP4015537A1 (en) 2015-12-01 2022-06-22 GlaxoSmithKline Intellectual Property Development Limited Combination treatments and uses and methods thereof
EP3366691A1 (en) 2015-12-03 2018-08-29 GlaxoSmithKline Intellectual Property Development Limited Cyclic purine dinucleotides as modulators of sting
WO2017098421A1 (en) 2015-12-08 2017-06-15 Glaxosmithkline Intellectual Property Development Limited Benzothiadiazine compounds
US20180364240A1 (en) * 2015-12-10 2018-12-20 Medimmune, Llc Methods for treatment and selection of patients responsive to immune mediated cancer therapy
KR102424513B1 (en) 2015-12-14 2022-07-25 마크로제닉스, 인크. Bispecific molecules with immunoreactivity with PD-1 and CTLA-4, and methods of use thereof
CN106939047B (en) 2016-01-04 2021-08-31 江苏怀瑜药业有限公司 PD-L1 antibody and preparation method thereof
EP3402503B1 (en) 2016-01-13 2020-10-21 Acerta Pharma B.V. Therapeutic combinations of an antifolate and a btk inhibitor
EP3417294B8 (en) 2016-02-15 2022-05-04 Astrazeneca AB Methods comprising fixed intermittent dosing of cediranib
WO2017153952A1 (en) 2016-03-10 2017-09-14 Glaxosmithkline Intellectual Property Development Limited 5-sulfamoyl-2-hydroxybenzamide derivatives
WO2017176925A1 (en) 2016-04-05 2017-10-12 Bristol-Myers Squibb Company Cytokine profiling analysis for predicting prognosis of a patient in need of an anti-cancer treatment
WO2017176565A1 (en) 2016-04-07 2017-10-12 Eli Lilly And Company Combinations of an anti-b7-h1 antibody and a cxcr4 peptide antagonist for treating a solid tumor
SG11201807474SA (en) * 2016-04-25 2018-11-29 Medimmune Llc Compositions comprising coformulation of anti-pd-l1 and anti-ctla-4 antibodies
JP2019516685A (en) 2016-05-05 2019-06-20 グラクソスミスクライン、インテレクチュアル、プロパティー、(ナンバー2)、リミテッドGlaxosmithkline Intellectual Property (No.2) Limited Enhancer of ZESTE Homolog 2 Inhibitor
WO2017205875A1 (en) 2016-05-27 2017-11-30 Dnatrix, Inc. Adenovirus and immunomodulator combination therapy
CN109476751B (en) 2016-05-27 2024-04-19 艾吉纳斯公司 Anti-TIM-3 antibodies and methods of use thereof
WO2017210453A1 (en) 2016-06-02 2017-12-07 Bristol-Myers Squibb Company Pd-1 blockade with nivolumab in refractory hodgkin's lymphoma
HUE063911T2 (en) 2016-06-02 2024-02-28 Bristol Myers Squibb Co Use of an anti-pd-1 antibody in combination with an anti-cd30 antibody in lymphoma treatment
KR102515509B1 (en) 2016-06-03 2023-03-28 브리스톨-마이어스 스큅 컴퍼니 Use of Anti-PD-1 Antibodies in the Treatment of Patients with Colorectal Cancer
WO2017210631A1 (en) 2016-06-03 2017-12-07 Bristol-Myers Squibb Company Anti-pd-1 antibody for use in a method of treatment of recurrent small cell lung cancer
CN109476753A (en) 2016-06-03 2019-03-15 百时美施贵宝公司 For treating the anti-PD-1 antibody of the method for tumour
CA3027045A1 (en) * 2016-06-08 2017-12-14 Abbvie Inc. Anti-b7-h3 antibodies and antibody drug conjugates
EP3468960B1 (en) 2016-06-08 2022-03-23 GlaxoSmithKline Intellectual Property Development Limited Chemical compounds as atf4 pathway inhibitors
WO2017212423A1 (en) 2016-06-08 2017-12-14 Glaxosmithkline Intellectual Property Development Limited Chemcical compounds
JP7185530B2 (en) 2016-06-13 2022-12-07 トルク セラピューティクス, インコーポレイテッド Methods and compositions for promoting immune cell function
RU2656181C1 (en) * 2016-07-13 2018-05-31 Закрытое Акционерное Общество "Биокад" Anti-pd-1 antibodies, method for their production, and method of application
GB201612520D0 (en) 2016-07-19 2016-08-31 F-Star Beta Ltd Binding molecules
US20190241573A1 (en) 2016-07-20 2019-08-08 Glaxosmithkline Intellectual Property Development Limited Isoquinoline derivatives as perk inhibitors
CN106243223B (en) * 2016-07-28 2019-03-05 北京百特美博生物科技有限公司 Anti-human PDL1 antibody and application thereof
US11312773B2 (en) * 2016-08-15 2022-04-26 Fuso Pharmaceutical Industries, Ltd. Anti-PD-L1 antibody
WO2018048975A1 (en) 2016-09-09 2018-03-15 Bristol-Myers Squibb Company Use of an anti-pd-1 antibody in combination with an anti-mesothelin antibody in cancer treatment
AU2017322501A1 (en) 2016-09-09 2019-03-28 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Combination of an anti-CD20 antibody, PI3 kinase-delta inhibitor, and anti-PD-1 or anti-PD-L1 antibody for treating hematological cancers
CA3037008A1 (en) 2016-09-27 2018-04-05 Oncologie, Inc. Methods for treating cancer with bavituximab based on levels of .beta.2-glycoprotein 1, and assays therefor
CA3039451A1 (en) 2016-10-06 2018-04-12 Pfizer Inc. Dosing regimen of avelumab for the treatment of cancer
AU2017343621B2 (en) 2016-10-11 2021-12-02 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
TWI788307B (en) 2016-10-31 2023-01-01 美商艾歐凡斯生物治療公司 Engineered artificial antigen presenting cells for tumor infiltrating lymphocyte expansion
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
WO2018098352A2 (en) 2016-11-22 2018-05-31 Jun Oishi Targeting kras induced immune checkpoint expression
US11299469B2 (en) 2016-11-29 2022-04-12 Sumitomo Dainippon Pharma Oncology, Inc. Naphthofuran derivatives, preparation, and methods of use thereof
KR20190090822A (en) 2016-12-01 2019-08-02 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 Combination therapy
AU2017369994A1 (en) 2016-12-01 2019-06-13 Glaxosmithkline Intellectual Property Development Limited Combination therapy
CA3045508A1 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods for modulation of car-t cells
MA50948A (en) 2016-12-07 2020-10-14 Agenus Inc ANTIBODIES AND METHODS OF USING THE SAME
PT3551660T (en) 2016-12-07 2023-11-30 Ludwig Inst For Cancer Res Ltd Anti-ctla-4 antibodies and methods of use thereof
CA3046963A1 (en) 2016-12-14 2018-06-21 Janssen Biotech, Inc. Cd8a-binding fibronectin type iii domains
WO2018111978A1 (en) 2016-12-14 2018-06-21 Janssen Biotech, Inc. Cd137 binding fibronectin type iii domains
US10597438B2 (en) 2016-12-14 2020-03-24 Janssen Biotech, Inc. PD-L1 binding fibronectin type III domains
WO2018112360A1 (en) 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Combination therapies for treating cancer
WO2018112364A1 (en) 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Combination therapies for treating melanoma
US11584733B2 (en) 2017-01-09 2023-02-21 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
US11034667B2 (en) 2017-01-09 2021-06-15 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
MX2019008346A (en) 2017-01-13 2019-09-09 Agenus Inc T cell receptors that bind to ny-eso-1 and methods of use thereof.
CN110325209A (en) 2017-02-24 2019-10-11 宏观基因有限公司 CD137 and the bi-specific binding molecule of tumour antigen and application thereof can be combined
WO2018161872A1 (en) * 2017-03-06 2018-09-13 江苏恒瑞医药股份有限公司 Anti-b7-h3 antibody, antigen-binding fragment thereof, and pharmaceutical use thereof
CA3055127A1 (en) * 2017-03-09 2018-09-13 Genmab A/S Antibodies against pd-l1
CA3058276A1 (en) 2017-03-30 2018-10-04 Merck Patent Gmbh Combination of an anti-pd-l1 antibody and a dna-pk inhibitor for the treatment of cancer
US11571459B2 (en) 2017-04-03 2023-02-07 Oncxerna Therapeutics, Inc. Methods for treating cancer using PS-targeting antibodies with immuno-oncology agents
MX2019012223A (en) 2017-04-13 2019-12-09 Agenus Inc Anti-cd137 antibodies and methods of use thereof.
KR20190137911A (en) 2017-04-21 2019-12-11 신라젠(주) Anticancer Vaccinia Virus and Gateway Inhibitor Combination Therapy
AR111651A1 (en) 2017-04-28 2019-08-07 Novartis Ag CONJUGATES OF ANTIBODIES THAT INCLUDE TOLL TYPE RECEIVER AGONISTS AND COMBINATION THERAPIES
TWI805582B (en) 2017-05-01 2023-06-21 美商艾吉納斯公司 Anti-tigit antibodies and methods of use thereof
CN110050000B (en) 2017-05-12 2022-07-26 苏州盛迪亚生物医药有限公司 Fusion protein containing TGF-beta receptor and medical application thereof
CA3062656A1 (en) 2017-05-17 2018-11-22 Boston Biomedical, Inc. Methods for treating cancer
CN110913911A (en) 2017-05-18 2020-03-24 特沙诺有限公司 Combination therapy for the treatment of cancer
WO2018225093A1 (en) 2017-06-07 2018-12-13 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as atf4 pathway inhibitors
JP2020522555A (en) 2017-06-09 2020-07-30 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited Combination therapy
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
SG11201912473PA (en) 2017-06-22 2020-01-30 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag Il-1beta binding antibodies for use in treating cancer
WO2018237173A1 (en) 2017-06-22 2018-12-27 Novartis Ag Antibody molecules to cd73 and uses thereof
US20190048072A1 (en) 2017-06-22 2019-02-14 Novartis Ag USE OF IL-1beta BINDING ANTIBODIES
WO2019006007A1 (en) 2017-06-27 2019-01-03 Novartis Ag Dosage regimens for anti-tim-3 antibodies and uses thereof
US20200140383A1 (en) 2017-07-03 2020-05-07 Glaxosmithkline Intellectual Property Development Limited 2-(4-chlorophenoxy)-n-((1 -(2-(4-chlorophenoxy)ethynazetidin-3-yl)methyl)acetamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases
US20210145771A1 (en) 2017-07-03 2021-05-20 Glaxosmithkline Intellectual Property Development Limited N-(3-(2-(4-chlorophenoxy)acetamido)bicyclo[1.1.1] pentan-1-yl)-2-cyclobutane-1- carboxamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases
US20200172617A1 (en) 2017-07-20 2020-06-04 Novartis Ag Dosage regimens of anti-lag-3 antibodies and uses thereof
WO2019021208A1 (en) 2017-07-27 2019-01-31 Glaxosmithkline Intellectual Property Development Limited Indazole derivatives useful as perk inhibitors
US11899017B2 (en) 2017-07-28 2024-02-13 Bristol-Myers Squibb Company Predictive peripheral blood biomarker for checkpoint inhibitors
WO2019025545A1 (en) 2017-08-04 2019-02-07 Genmab A/S Binding agents binding to pd-l1 and cd137 and use thereof
MX2020001980A (en) 2017-08-28 2020-03-24 Bristol Myers Squibb Co Tim-3 antagonists for the treatment and diagnosis of cancers.
CA3073055A1 (en) 2017-09-04 2019-03-07 Agenus Inc. T cell receptors that bind to mixed lineage leukemia (mll)-specific phosphopeptides and methods of use thereof
TW201922721A (en) 2017-09-07 2019-06-16 英商葛蘭素史克智慧財產發展有限公司 Chemical compounds
WO2019053617A1 (en) 2017-09-12 2019-03-21 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
US11497756B2 (en) 2017-09-12 2022-11-15 Sumitomo Pharma Oncology, Inc. Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib
EP3697442A4 (en) 2017-09-30 2021-07-07 Tesaro, Inc. Combination therapies for treating cancer
CA3076859A1 (en) 2017-10-06 2019-04-11 Tesaro, Inc. Combination therapies and uses thereof
AU2018353432A1 (en) 2017-10-19 2020-04-23 Debiopharm International S.A. Combination product for the treatment of cancer
US20210040205A1 (en) 2017-10-25 2021-02-11 Novartis Ag Antibodies targeting cd32b and methods of use thereof
WO2019094265A1 (en) * 2017-11-10 2019-05-16 Armo Biosciences, Inc. Pd1 polypeptide binding molecules
WO2019108900A1 (en) 2017-11-30 2019-06-06 Novartis Ag Bcma-targeting chimeric antigen receptor, and uses thereof
CN108144745B (en) * 2017-12-20 2020-06-16 天康生物股份有限公司 Separation device and method for reducing endotoxin content of live brucellosis vaccine
US20200368268A1 (en) 2018-01-08 2020-11-26 Novartis Ag Immune-enhancing rnas for combination with chimeric antigen receptor therapy
CN112004537A (en) 2018-01-09 2020-11-27 穿梭药业公司 Selective histone deacetylase inhibitors for the treatment of human diseases
JP2021510078A (en) * 2018-01-10 2021-04-15 江▲蘇▼恒瑞医▲薬▼股▲フン▼有限公司Jiangsu Hengrui Medicine Co., Ltd. PD-L1 antibody, its antigen-binding fragment, and its pharmaceutical use
AU2019215031A1 (en) 2018-01-31 2020-08-20 Novartis Ag Combination therapy using a chimeric antigen receptor
WO2019152743A1 (en) 2018-01-31 2019-08-08 Celgene Corporation Combination therapy using adoptive cell therapy and checkpoint inhibitor
US20200399383A1 (en) 2018-02-13 2020-12-24 Novartis Ag Chimeric antigen receptor therapy in combination with il-15r and il15
AU2019233596A1 (en) 2018-03-14 2020-10-08 Merck Patent Gmbh Compounds and uses thereof to treat tumors in a subject
US12110337B2 (en) 2018-04-04 2024-10-08 Bristol-Myers Squibb Company Anti-CD27 antibodies and uses thereof
WO2019193541A1 (en) 2018-04-06 2019-10-10 Glaxosmithkline Intellectual Property Development Limited Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors
WO2019193540A1 (en) 2018-04-06 2019-10-10 Glaxosmithkline Intellectual Property Development Limited Heteroaryl derivatives of formula (i) as atf4 inhibitors
US20210147547A1 (en) 2018-04-13 2021-05-20 Novartis Ag Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof
BR112020021271A2 (en) 2018-04-17 2021-01-26 Celldex Therapeutics, Inc. bispecific constructs and anti-cd27 and anti-pd-l1 antibodies
JP7516254B2 (en) 2018-04-18 2024-07-16 ゼンコア インコーポレイテッド IL-15/IL-15RA HETERODIMERIC FC FUSION PROTEINS AND USES THEREOF
US11524991B2 (en) 2018-04-18 2022-12-13 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
KR20210005096A (en) * 2018-04-25 2021-01-13 메디뮨 리미티드 Formulation of human anti-PD-L1 antibody
JP2021522239A (en) 2018-04-26 2021-08-30 アジェナス インコーポレイテッド Heat shock protein-binding peptide composition and how to use it
WO2019219658A1 (en) 2018-05-15 2019-11-21 Medimmune Limited Treatment of cancer
AR126019A1 (en) 2018-05-30 2023-09-06 Novartis Ag ANTIBODIES AGAINST ENTPD2, COMBINATION THERAPIES AND METHODS OF USE OF ANTIBODIES AND COMBINATION THERAPIES
US20210214459A1 (en) 2018-05-31 2021-07-15 Novartis Ag Antibody molecules to cd73 and uses thereof
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
CN112424167A (en) 2018-07-09 2021-02-26 葛兰素史密斯克莱知识产权发展有限公司 Chemical compound
JOP20210001A1 (en) 2018-07-10 2021-01-05 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases
AR116109A1 (en) 2018-07-10 2021-03-31 Novartis Ag DERIVATIVES OF 3- (5-AMINO-1-OXOISOINDOLIN-2-IL) PIPERIDINE-2,6-DIONA AND USES OF THE SAME
WO2020014543A2 (en) 2018-07-11 2020-01-16 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof
GB201811408D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd CD137 Binding Molecules
WO2020031107A1 (en) 2018-08-08 2020-02-13 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
TW202031273A (en) 2018-08-31 2020-09-01 美商艾歐凡斯生物治療公司 Treatment of nsclc patients refractory for anti-pd-1 antibody
WO2020060771A1 (en) * 2018-09-18 2020-03-26 Vanderbilt University Human monoclonal antibodies to staphylococcal aureus isd proteins and uses thereof
WO2020061429A1 (en) 2018-09-20 2020-03-26 Iovance Biotherapeutics, Inc. Expansion of tils from cryopreserved tumor samples
WO2020064971A1 (en) 2018-09-26 2020-04-02 Merck Patent Gmbh Combination of a pd-1 antagonist, an atr inhibitor and a platinating agent for the treatment of cancer
SG11202103192RA (en) 2018-10-03 2021-04-29 Xencor Inc Il-12 heterodimeric fc-fusion proteins
JP2022512642A (en) 2018-10-09 2022-02-07 ブリストル-マイヤーズ スクイブ カンパニー Anti-MerTK antibody to treat cancer
MA53862A (en) 2018-10-12 2022-01-19 Xencor Inc FC FUSION PROTEINS OF IL-15/IL-15RALPHA TARGETTING PD-1 AND USES IN COMBINATION THERAPIES INVOLVING THE SAME
JP2022504905A (en) 2018-10-16 2022-01-13 ノバルティス アーゲー Tumor mutation loading alone or in combination with immune markers as a biomarker to predict response to targeted therapy
WO2020081493A1 (en) 2018-10-16 2020-04-23 Molecular Templates, Inc. Pd-l1 binding proteins
US11798653B2 (en) 2018-10-18 2023-10-24 Medimmune, Llc Methods for determining treatment for cancer patients
BR112021007517A2 (en) 2018-10-22 2021-10-26 Glaxosmithkline Intellectual Property Development Limited DOSAGE
EP3873532A1 (en) 2018-10-31 2021-09-08 Novartis AG Dc-sign antibody drug conjugates
MX2021005018A (en) 2018-11-09 2021-06-15 Jiangsu Hengrui Medicine Co Tgf-î² receptor fusion protein pharmaceutical composition and use thereof.
CA3119563A1 (en) 2018-11-14 2020-05-22 Bayer Aktiengesellschaft Pharmaceutical combination of anti-ceacam6 and either anti-pd-1 or anti-pd-l1 antibodies for the treatment of cancer
TW202028222A (en) 2018-11-14 2020-08-01 美商Ionis製藥公司 Modulators of foxp3 expression
MX2021005808A (en) 2018-11-20 2021-07-02 Univ Cornell Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer.
CN113453678A (en) 2018-11-26 2021-09-28 德彪药业国际股份公司 Combination therapy for HIV infection
AR117206A1 (en) 2018-11-30 2021-07-21 Glaxosmithkline Ip Dev Ltd OCTAHYDROPIRROLO [2,1-B] [1,3] THIAZEPIN-7-CARBOXAMIDE DERIVATIVES USEFUL IN HIV THERAPY AND FOR THE TREATMENT OF CANCER
US11034710B2 (en) 2018-12-04 2021-06-15 Sumitomo Dainippon Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
CN113438961A (en) 2018-12-20 2021-09-24 Xencor股份有限公司 Targeting heterodimeric Fc fusion proteins containing IL-15/IL-15R α and NKG2D antigen binding domains
KR20210106437A (en) 2018-12-20 2021-08-30 노파르티스 아게 Dosage regimens and pharmaceutical combinations comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
US20220370606A1 (en) 2018-12-21 2022-11-24 Pfizer Inc. Combination Treatments Of Cancer Comprising A TLR Agonist
KR20210107730A (en) 2018-12-21 2021-09-01 노파르티스 아게 Use of IL-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome
WO2020128613A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
US20220056123A1 (en) 2018-12-21 2022-02-24 Novartis Ag Use of il-1beta binding antibodies
AU2019408408A1 (en) 2018-12-21 2021-06-03 Valerio Therapeutics New conjugated nucleic acid molecules and their uses
CN113227135A (en) 2018-12-28 2021-08-06 斯帕克斯治疗公司 Binding molecules specific for claudin 18.2, compositions and methods thereof for the treatment of cancer and other diseases
WO2020160375A1 (en) 2019-02-01 2020-08-06 Glaxosmithkline Intellectual Property Development Limited Combination treatments for cancer comprising belantamab mafodotin and an anti ox40 antibody and uses and methods thereof
MX2021009371A (en) 2019-02-12 2021-09-10 Sumitomo Pharma Oncology Inc Formulations comprising heterocyclic protein kinase inhibitors.
EP3924521A4 (en) 2019-02-15 2023-03-29 IncellDx, Inc. Assaying bladder-associated samples, identifying and treating bladder-associated neoplasia, and kits for use therein
CN113490528A (en) 2019-02-15 2021-10-08 诺华股份有限公司 3- (1-oxo-5- (piperidine-4-yl) isoindoline-2-yl) piperidine-2, 6-dione derivatives and uses thereof
EP3924055B1 (en) 2019-02-15 2024-04-03 Novartis AG Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
PT3927370T (en) 2019-02-19 2024-06-03 Turnstone Biologics Corp Methods for producing autologous t cells useful to treat cancers and compositions thereof
US11793802B2 (en) 2019-03-20 2023-10-24 Sumitomo Pharma Oncology, Inc. Treatment of acute myeloid leukemia (AML) with venetoclax failure
MX2021011289A (en) 2019-03-22 2021-11-03 Sumitomo Pharma Oncology Inc Compositions comprising pkm2 modulators and methods of treatment using the same.
EP3946437A1 (en) 2019-03-29 2022-02-09 Myst Therapeutics, LLC Ex vivo methods for producing a t cell therapeutic and related compositions and methods
SG11202109441UA (en) 2019-04-12 2021-09-29 Vascular Biogenics Ltd Methods of anti-tumor therapy
US20220211847A1 (en) 2019-05-06 2022-07-07 Medimmune Limited Combination of monalizumab, durvalumab, chemotherapy and bevacizumab or cetuximab for the treatment of colorectal cancer
KR20220026585A (en) 2019-06-26 2022-03-04 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 IL1RAP binding protein
CA3145864A1 (en) 2019-07-03 2021-01-07 Sumitomo Dainippon Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof
CA3152027A1 (en) 2019-08-30 2021-03-04 Agenus Inc. Anti-cd96 antibodies and methods of use thereof
KR20220058601A (en) 2019-09-05 2022-05-09 아스트라제네카 아베 Compositions and methods for treating expanded stage small cell lung cancer (ES-SCLC)
WO2021043961A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy
TW202124446A (en) 2019-09-18 2021-07-01 瑞士商諾華公司 Combination therapies with entpd2 antibodies
JP2022548078A (en) 2019-09-18 2022-11-16 モレキュラー テンプレーツ,インク. PD-L1 binding molecules containing Shiga toxin A subunit scaffolds
WO2021055816A1 (en) 2019-09-18 2021-03-25 Molecular Templates, Inc. Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds
EP4031578A1 (en) 2019-09-18 2022-07-27 Novartis AG Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
US20230405105A1 (en) 2019-09-20 2023-12-21 Transgene Sa Combination of a poxvirus encoding hpv polypeptides with an anti-pd-l1 antibody
EP4034562A2 (en) 2019-09-27 2022-08-03 GlaxoSmithKline Intellectual Property Development Limited Antigen binding proteins
EP4023672A1 (en) * 2019-09-30 2022-07-06 Harbour Biomed (Shanghai) Co., Ltd Anti-pd-l1 antigen binding protein, and application thereof
CA3157024A1 (en) 2019-10-03 2021-04-08 Xencor, Inc. Targeted il-12 heterodimeric fc-fusion proteins
TW202128757A (en) 2019-10-11 2021-08-01 美商建南德克公司 Pd-1 targeted il-15/il-15ralpha fc fusion proteins with improved properties
US11781138B2 (en) 2019-10-14 2023-10-10 Aro Biotherapeutics Company FN3 domain-siRNA conjugates and uses thereof
WO2021076546A1 (en) 2019-10-14 2021-04-22 Aro Biotherapeutics Company Cd71 binding fibronectin type iii domains
KR20220103947A (en) 2019-10-21 2022-07-25 노파르티스 아게 Combination Therapy with Venetoclax and TIM-3 Inhibitors
AU2020370832A1 (en) 2019-10-21 2022-05-19 Novartis Ag TIM-3 inhibitors and uses thereof
CA3151629A1 (en) 2019-11-07 2021-05-14 Laura E. BENJAMIN Classification of tumor microenvironments
US20230000864A1 (en) 2019-11-22 2023-01-05 Sumitomo Pharma Oncology, Inc. Solid dose pharmaceutical composition
WO2021108727A1 (en) 2019-11-27 2021-06-03 Myst Therapeutics, Inc. Method of producing tumor-reactive t cell composition using modulatory agents
MX2022007759A (en) 2019-12-20 2022-07-19 Novartis Ag Combination of anti tim-3 antibody mbg453 and anti tgf-beta antibody nis793, with or without decitabine or the anti pd-1 antibody spartalizumab, for treating myelofibrosis and myelodysplastic syndrome.
KR20220128389A (en) 2020-01-17 2022-09-20 노파르티스 아게 A combination comprising a TIM-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia
CA3167689A1 (en) 2020-01-28 2021-08-05 Glaxosmithkline Intellectual Property Development Limited Combination treatments and uses and methods thereof
AU2021227687B2 (en) 2020-02-26 2023-02-23 Vir Biotechnology, Inc. Antibodies against SARS-CoV-2 and methods of using the same
CA3172902A1 (en) 2020-02-27 2021-09-02 Myst Therapeutics, Llc Methods for ex vivo enrichment and expansion of tumor reactive t cells and related compositions thereof
WO2021194942A1 (en) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Anti-ccr8 antibodies for treating cancer
CN115461362A (en) 2020-04-14 2022-12-09 葛兰素史密斯克莱知识产权发展有限公司 Cancer combination therapy based on ICOS antibody and PD-L1 antibody TGF-beta receptor fusion protein
CA3176356A1 (en) 2020-04-22 2021-10-28 Anne BROOKS Systems and methods for coordinating manufacturing of cells for patient-specific immunotherapy
US20210332105A1 (en) 2020-04-24 2021-10-28 Astrazeneca Ab Compositions and methods of treating cancer with chimeric antigen receptors
AU2021269832B2 (en) 2020-05-12 2024-09-19 Astrazeneca Ab Methods and combinations for the treatment of cancer using immune checkpoint inhibitor antibodies
US20230374597A1 (en) 2020-05-12 2023-11-23 Astrazeneca Ab Biomarkers for predicting overall survival in recorrent/metastatic head and neck squamous cell carcinoma
JP2023526400A (en) 2020-05-21 2023-06-21 アストラゼネカ・アクチエボラーグ Mutational Burden Associated with Immunotherapy Susceptibility in Locally Advanced or Metastatic Urothelial Cancer
TW202214857A (en) 2020-06-19 2022-04-16 法商昂席歐公司 New conjugated nucleic acid molecules and their uses
CN115916199A (en) 2020-06-23 2023-04-04 诺华股份有限公司 Dosing regimens comprising 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione derivatives
US20230250173A1 (en) 2020-07-01 2023-08-10 Pfizer Inc. Biomarkers for pd-1 axis binding antagonist therapy
EP4188549A1 (en) 2020-08-03 2023-06-07 Novartis AG Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
JP2023544635A (en) 2020-10-12 2023-10-24 アストラゼネカ・アクチエボラーグ Adjuvant durvalumab in combination with chemotherapy for the treatment of cancer
WO2022086957A1 (en) 2020-10-20 2022-04-28 Genentech, Inc. Peg-conjugated anti-mertk antibodies and methods of use
WO2022097060A1 (en) 2020-11-06 2022-05-12 Novartis Ag Cd19 binding molecules and uses thereof
TW202237119A (en) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Alk-5 inhibitors and uses thereof
EP4263600A1 (en) 2020-12-18 2023-10-25 Century Therapeutics, Inc. Chimeric antigen receptor systems with adaptable receptor specificity
CN116744971A (en) * 2021-01-04 2023-09-12 上海翰森生物医药科技有限公司 anti-ERBB 3 receptor antibody or antigen binding fragment thereof and medical application thereof
EP4284510A1 (en) 2021-01-29 2023-12-06 Novartis AG Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof
TW202241508A (en) 2021-01-29 2022-11-01 美商艾歐凡斯生物治療公司 Cytokine associated tumor infiltrating lymphocytes compositions and methods
US20240139198A1 (en) 2021-02-10 2024-05-02 Curon Biopharmaceutical (Shanghai) Co., Limited Method and combination for treating tumors
BR112023017296A2 (en) 2021-03-02 2023-11-14 Glaxosmithkline Ip Dev Ltd SUBSTITUTED PYRIDIINES AS DNMT1 INHIBITORS
WO2022195551A1 (en) 2021-03-18 2022-09-22 Novartis Ag Biomarkers for cancer and methods of use thereof
IL306090A (en) 2021-03-25 2023-11-01 Oncxerna Therapeutics Inc Targeted therapies in cancer
MX2023011332A (en) 2021-03-26 2023-10-03 Astrazeneca Ab Combination treatments for melanoma.
EP4314060A1 (en) 2021-03-31 2024-02-07 GlaxoSmithKline Intellectual Property Development Limited Antigen binding proteins and combinations thereof
TW202304979A (en) 2021-04-07 2023-02-01 瑞士商諾華公司 USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
AU2022253351A1 (en) 2021-04-09 2023-10-12 Ose Immunotherapeutics New scaffold for bifunctional molecules with improved properties
WO2022214652A1 (en) 2021-04-09 2022-10-13 Ose Immunotherapeutics Scaffold for bifunctioanl molecules comprising pd-1 or cd28 and sirp binding domains
PE20240327A1 (en) 2021-04-13 2024-02-22 Nuvalent Inc HETEROCYCLES WITH AMINO SUBSTITUTION TO TREAT CANCERS WITH EGFR MUTATIONS
BR112023021325A2 (en) 2021-04-14 2023-12-19 Aro Biotherapeutics Company CD71-BINDING TYPE III FIBRONECTIN DOMAINS
WO2022226539A1 (en) * 2021-04-23 2022-10-27 Immunome, Inc. Methods of administering antibodies against sars-cov-2 spike protein
AR125874A1 (en) 2021-05-18 2023-08-23 Novartis Ag COMBINATION THERAPIES
CN117396222A (en) 2021-05-21 2024-01-12 天津立博美华基因科技有限责任公司 Pharmaceutical combination and use thereof
BR112023023833A2 (en) 2021-05-24 2024-01-30 Astrazeneca Ab COMPOSITIONS AND METHODS FOR TREATMENT OF LUNG CANCER
CN117412767A (en) 2021-05-25 2024-01-16 雪绒花免疫公司 C-X-C motif chemokine receptor 6 (CXCR 6) binding molecules and methods of use thereof
WO2022247972A2 (en) 2021-05-26 2022-12-01 Centro De Inmunologia Molecular Use of therapeutic compositions for the treatment of patients with tumours of epithelial origin
IL309662A (en) 2021-07-02 2024-02-01 Univ Yale Compositions and methods for treating cancers
EP4395832A1 (en) 2021-08-31 2024-07-10 Yale University Compositions and methods for treating cancers
KR20240051162A (en) 2021-09-02 2024-04-19 도이체스크레브스포르슝스젠트룸스티프퉁데스외펜트리헨레크츠 Anti-CECAM6 antibody with reduced side effects
CN118159568A (en) 2021-10-21 2024-06-07 杭州阿诺生物医药科技有限公司 Fusion polypeptide and application thereof
IL313439A (en) 2021-12-16 2024-08-01 Valerio Therapeutics New conjugated nucleic acid molecules and their uses
WO2023147488A1 (en) 2022-01-28 2023-08-03 Iovance Biotherapeutics, Inc. Cytokine associated tumor infiltrating lymphocytes compositions and methods
WO2023154799A1 (en) 2022-02-14 2023-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Combination immunotherapy for treating cancer
IL315265A (en) 2022-03-03 2024-10-01 Pfizer Inc Multispecific antibodies and uses thereof
WO2023170008A1 (en) 2022-03-07 2023-09-14 Astrazeneca Ab Method for predicting patient response to immunotherapy
WO2023174210A1 (en) 2022-03-14 2023-09-21 Laekna Limited Combination treatment for cancer
AU2022447580A1 (en) 2022-03-18 2024-10-17 Astrazeneca Ab Methods of treating biliary tract cancer using anti-pd-l1 antibody in combination with chemotherapy
WO2023201369A1 (en) 2022-04-15 2023-10-19 Iovance Biotherapeutics, Inc. Til expansion processes using specific cytokine combinations and/or akti treatment
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
AR129423A1 (en) 2022-05-27 2024-08-21 Viiv Healthcare Co USEFUL COMPOUNDS IN HIV THERAPY
WO2024003241A1 (en) 2022-06-30 2024-01-04 Astrazeneca Ab Treatment for immuno-oncology resistant subjects with an anti pd-l1 antibody an antisense targeted to stat3 and an inhibitor of ctla-4
WO2024030906A2 (en) * 2022-08-05 2024-02-08 Hbm Alpha Therapeutics, Inc. Anti-corticotropin-releasing hormone antibodies and polycystic ovary syndrome
WO2024040175A1 (en) 2022-08-18 2024-02-22 Pulmatrix Operating Company, Inc. Methods for treating cancer using inhaled angiogenesis inhibitor
TW202428254A (en) 2022-09-09 2024-07-16 瑞典商阿斯特捷利康公司 Compositions and methods for treating advanced solid tumors
US20240190982A1 (en) 2022-11-03 2024-06-13 Incyte Corporation Combination therapies comprising an anti-gitr antibody for treating cancers
WO2024112571A2 (en) 2022-11-21 2024-05-30 Iovance Biotherapeutics, Inc. Two-dimensional processes for the expansion of tumor infiltrating lymphocytes and therapies therefrom
WO2024115966A2 (en) 2022-12-01 2024-06-06 Innate Pharma Compositions and methods for neoadjuvant treatment in cancer
WO2024151885A1 (en) 2023-01-13 2024-07-18 Iovance Biotherapeutics, Inc. Use of til as maintenance therapy for nsclc patients who achieved pr/cr after prior therapy
WO2024163477A1 (en) 2023-01-31 2024-08-08 University Of Rochester Immune checkpoint blockade therapy for treating staphylococcus aureus infections
WO2024192051A1 (en) 2023-03-13 2024-09-19 Turnstone Biologics Corp. Composition of selected tumor infiltrating lymphocytes and related methods of producing and using the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050226883A1 (en) * 2004-02-06 2005-10-13 Paul Averback Humanized antibody
US20090055944A1 (en) * 2005-07-01 2009-02-26 Medarex, Inc. Human monoclonal antibodies to be programmed death ligand 1 (pd-l1)

Family Cites Families (142)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3180193A (en) 1963-02-25 1965-04-27 Benedict David Machines for cutting lengths of strip material
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
FR2413974A1 (en) 1978-01-06 1979-08-03 David Bernard DRYER FOR SCREEN-PRINTED SHEETS
US4263428A (en) 1978-03-24 1981-04-21 The Regents Of The University Of California Bis-anthracycline nucleic acid function inhibitors and improved method for administering the same
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
EP0052322B1 (en) 1980-11-10 1985-03-27 Gersonde, Klaus, Prof. Dr. Method of preparing lipid vesicles by ultrasonic treatment, the use of this method and apparatus for its application
IE52535B1 (en) 1981-02-16 1987-12-09 Ici Plc Continuous release pharmaceutical compositions
US4474893A (en) 1981-07-01 1984-10-02 The University of Texas System Cancer Center Recombinant monoclonal antibodies
US4714681A (en) 1981-07-01 1987-12-22 The Board Of Reagents, The University Of Texas System Cancer Center Quadroma cells and trioma cells and methods for the production of same
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
EP0088046B1 (en) 1982-02-17 1987-12-09 Ciba-Geigy Ag Lipids in the aqueous phase
DE3218121A1 (en) 1982-05-14 1983-11-17 Leskovar, Peter, Dr.-Ing., 8000 München Pharmaceutical compositions for tumour treatment
EP0102324A3 (en) 1982-07-29 1984-11-07 Ciba-Geigy Ag Lipids and surfactants in an aqueous medium
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US4675187A (en) 1983-05-16 1987-06-23 Bristol-Myers Company BBM-1675, a new antibiotic complex
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
HUT35524A (en) 1983-08-02 1985-07-29 Hoechst Ag Process for preparing pharmaceutical compositions containing regulatory /regulative/ peptides providing for the retarded release of the active substance
ATE59966T1 (en) 1983-09-26 1991-02-15 Ehrenfeld Udo MEDICATION AND PRODUCT FOR THE DIAGNOSIS AND THERAPY OF TUMORS AND FOR THE TREATMENT OF WEAKNESSES IN THE CELLULAR AND HUMORAL IMMUNE DEFENSE.
US4615885A (en) 1983-11-01 1986-10-07 Terumo Kabushiki Kaisha Pharmaceutical composition containing urokinase
US4681581A (en) 1983-12-05 1987-07-21 Coates Fredrica V Adjustable size diaper and folding method therefor
US4740461A (en) 1983-12-27 1988-04-26 Genetics Institute, Inc. Vectors and methods for transformation of eucaryotic cells
US4735210A (en) 1985-07-05 1988-04-05 Immunomedics, Inc. Lymphographic and organ imaging method and kit
US5776093A (en) 1985-07-05 1998-07-07 Immunomedics, Inc. Method for imaging and treating organs and tissues
US5101827A (en) 1985-07-05 1992-04-07 Immunomedics, Inc. Lymphographic and organ imaging method and kit
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
WO1987006265A1 (en) 1986-04-17 1987-10-22 Kyowa Hakko Kogyo Co., Ltd. Novel compounds dc-88a and dc-89a1 and process for their preparation
US4959455A (en) 1986-07-14 1990-09-25 Genetics Institute, Inc. Primate hematopoietic growth factors IL-3 and pharmaceutical compositions
US4912040A (en) 1986-11-14 1990-03-27 Genetics Institute, Inc. Eucaryotic expression system
IL85035A0 (en) 1987-01-08 1988-06-30 Int Genetic Eng Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same
WO1988007089A1 (en) 1987-03-18 1988-09-22 Medical Research Council Altered antibodies
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
US5648471A (en) 1987-12-03 1997-07-15 Centocor, Inc. One vial method for labeling antibodies with Technetium-99m
US4925648A (en) 1988-07-29 1990-05-15 Immunomedics, Inc. Detection and treatment of infectious and inflammatory lesions
US5601819A (en) 1988-08-11 1997-02-11 The General Hospital Corporation Bispecific antibodies for selective immune regulation and for selective immune cell binding
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
US5175384A (en) 1988-12-05 1992-12-29 Genpharm International Transgenic mice depleted in mature t-cells and methods for making transgenic mice
DE3920358A1 (en) 1989-06-22 1991-01-17 Behringwerke Ag BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE
DE69029036T2 (en) 1989-06-29 1997-05-22 Medarex Inc SPECIFIC REAGENTS FOR AIDS THERAPY
ATE172879T1 (en) 1989-08-09 1998-11-15 Rhomed Inc DIRECT RADIO LABELING OF ANTIBODIES AND OTHER PROTEINS USING TECHNETIUM OR RHENIUM
JP2840866B2 (en) 1989-11-28 1998-12-24 日本ゼオン株式会社 Adhesive composition of nitrile group-containing highly saturated copolymer rubber and organic synthetic fiber
JP3068180B2 (en) 1990-01-12 2000-07-24 アブジェニックス インコーポレイテッド Generation of heterologous antibodies
US6673986B1 (en) 1990-01-12 2004-01-06 Abgenix, Inc. Generation of xenogeneic antibodies
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5151510A (en) 1990-04-20 1992-09-29 Applied Biosystems, Inc. Method of synethesizing sulfurized oligonucleotide analogs
FR2664073A1 (en) 1990-06-29 1992-01-03 Thomson Csf MEANS FOR MARKING OBJECTS, METHOD FOR PRODUCING THE SAME, AND DEVICE FOR READING.
CA2086417C (en) 1990-06-29 1999-07-06 Biosource Technologies, Inc. Melanin production by transformed organisms
US6300129B1 (en) 1990-08-29 2001-10-09 Genpharm International Transgenic non-human animals for producing heterologous antibodies
ATE352612T1 (en) 1990-08-29 2007-02-15 Pharming Intellectual Pty Bv HOMOLOGOUS RECOMBINATION IN MAMMAL CELLS
US5874299A (en) 1990-08-29 1999-02-23 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
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5789650A (en) 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
ATE158021T1 (en) 1990-08-29 1997-09-15 Genpharm Int PRODUCTION AND USE OF NON-HUMAN TRANSGENT ANIMALS FOR THE PRODUCTION OF HETEROLOGUE ANTIBODIES
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US6255458B1 (en) 1990-08-29 2001-07-03 Genpharm International High affinity human antibodies and human antibodies against digoxin
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5633425A (en) 1990-08-29 1997-05-27 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
US5194594A (en) 1990-09-07 1993-03-16 Techniclone, Inc. Modified antibodies
ATE160379T1 (en) 1990-10-29 1997-12-15 Chiron Corp BISPECIFIC ANTIBODIES, METHOD FOR THE PRODUCTION THEREOF AND USES THEREOF
WO1992019973A1 (en) 1991-04-26 1992-11-12 Surface Active Limited Novel antibodies, and methods for their use
WO1992022670A1 (en) 1991-06-12 1992-12-23 Genpharm International, Inc. Early detection of transgenic embryos
WO1992022653A1 (en) 1991-06-14 1992-12-23 Genentech, Inc. Method for making humanized antibodies
AU2235992A (en) 1991-06-14 1993-01-12 Genpharm International, Inc. Transgenic immunodeficient non-human animals
AU2515992A (en) 1991-08-20 1993-03-16 Genpharm International, Inc. Gene targeting in animal cells using isogenic dna constructs
EP0617706B1 (en) 1991-11-25 2001-10-17 Enzon, Inc. Multivalent antigen-binding proteins
JPH07503132A (en) 1991-12-17 1995-04-06 ジェンファーム インターナショナル,インコーポレイティド Transgenic non-human animals capable of producing xenoantibodies
CA2452130A1 (en) 1992-03-05 1993-09-16 Francis J. Burrows Methods and compositions for targeting the vasculature of solid tumors
AU4116793A (en) 1992-04-24 1993-11-29 Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
CA2135313A1 (en) 1992-06-18 1994-01-06 Theodore Choi Methods for producing transgenic non-human animals harboring a yeast artificial chromosome
ES2301158T3 (en) 1992-07-24 2008-06-16 Amgen Fremont Inc. XENOGENIC ANTIBODY PRODUCTION.
WO1994004690A1 (en) 1992-08-17 1994-03-03 Genentech, Inc. Bispecific immunoadhesins
WO1994013804A1 (en) 1992-12-04 1994-06-23 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US5981175A (en) 1993-01-07 1999-11-09 Genpharm Internation, Inc. Methods for producing recombinant mammalian cells harboring a yeast artificial chromosome
JPH08509612A (en) 1993-04-26 1996-10-15 ジェンファーム インターナショナル インコーポレイテッド Transgenic non-human animal capable of producing heterologous antibody
US5885573A (en) 1993-06-01 1999-03-23 Arch Development Corporation Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies
CA2163345A1 (en) 1993-06-16 1994-12-22 Susan Adrienne Morgan Antibodies
US5625825A (en) 1993-10-21 1997-04-29 Lsi Logic Corporation Random number generating apparatus for an interface unit of a carrier sense with multiple access and collision detect (CSMA/CD) ethernet data network
JPH07309761A (en) 1994-05-20 1995-11-28 Kyowa Hakko Kogyo Co Ltd Method for stabilizing duocamycin derivative
US5643763A (en) 1994-11-04 1997-07-01 Genpharm International, Inc. Method for making recombinant yeast artificial chromosomes by minimizing diploid doubling during mating
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
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
AU2466895A (en) 1995-04-28 1996-11-18 Abgenix, Inc. Human antibodies derived from immunized xenomice
TW311927B (en) 1995-07-11 1997-08-01 Minnesota Mining & Mfg
DE69636868T2 (en) 1995-08-29 2007-10-25 Kirin Beer Kabushiki Kaisha CHIMERIC ANIMAL AND METHOD FOR THE PRODUCTION THEREOF
GB9624482D0 (en) 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
KR19990082463A (en) 1996-02-13 1999-11-25 돈 리사 로얄 Quinazolin derivatives as vascular endothelial growth factor inhibitors
CN1116286C (en) 1996-03-05 2003-07-30 曾尼卡有限公司 4-anilinoquinazoline derivatives
EP0904107B1 (en) 1996-03-18 2004-10-20 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
WO1998023289A1 (en) 1996-11-27 1998-06-04 The General Hospital Corporation MODULATION OF IgG BINDING TO FcRn
KR20080059467A (en) 1996-12-03 2008-06-27 아브게닉스, 인크. Transgenic mammals having human ig loci including plural vh and vk regions and antibodies produced therefrom
WO1998035985A1 (en) 1997-02-12 1998-08-20 The Regents Of The University Of Michigan Protein markers for lung cancer and use thereof
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
GB9714249D0 (en) 1997-07-08 1997-09-10 Angiogene Pharm Ltd Vascular damaging agents
US6528624B1 (en) 1998-04-02 2003-03-04 Genentech, Inc. Polypeptide variants
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
DK2180007T4 (en) 1998-04-20 2017-11-27 Roche Glycart Ag Glycosylation technique for antibodies to enhance antibody-dependent cell cytotoxicity
GB9809951D0 (en) 1998-05-08 1998-07-08 Univ Cambridge Tech Binding molecules
WO2000034784A1 (en) 1998-12-10 2000-06-15 Phylos, Inc. Protein scaffolds for antibody mimics and other binding proteins
GB9900334D0 (en) 1999-01-07 1999-02-24 Angiogene Pharm Ltd Tricylic vascular damaging agents
GB9900752D0 (en) 1999-01-15 1999-03-03 Angiogene Pharm Ltd Benzimidazole vascular damaging agents
KR20060067983A (en) 1999-01-15 2006-06-20 제넨테크, 인크. Polypeptide variants with altered effector function
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
KR100838617B1 (en) 1999-02-10 2008-06-16 아스트라제네카 아베 Quinazoline derivatives as angiogenesis inhibitors
EP2275541B1 (en) 1999-04-09 2016-03-23 Kyowa Hakko Kirin Co., Ltd. Method for controlling the activity of immunologically functional molecule
US6833268B1 (en) 1999-06-10 2004-12-21 Abgenix, Inc. Transgenic animals for producing specific isotypes of human antibodies via non-cognate switch regions
US7504256B1 (en) 1999-10-19 2009-03-17 Kyowa Hakko Kogyo Co., Ltd. Process for producing polypeptide
PT1244647E (en) 1999-11-05 2006-10-31 Astrazeneca Ab QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
ME00415B (en) 2000-02-15 2011-10-10 Pharmacia & Upjohn Co Llc Pyrrole substituted 2-indolinone protein kinase inhibitors
IL152682A0 (en) 2000-05-31 2003-06-24 Astrazeneca Ab Indole derivatives with vascular damaging activity
UA73993C2 (en) 2000-06-06 2005-10-17 Астразенека Аб Quinazoline derivatives for the treatment of tumours and a pharmaceutical composition
CN1255391C (en) 2000-07-07 2006-05-10 安吉奥金尼药品有限公司 COLCHINOL derivatives as vascular damaging agents
PL359181A1 (en) 2000-07-07 2004-08-23 Angiogene Pharmaceuticals Limited Colchinol derivatives as angiogenesis inhibitors
EA013224B1 (en) 2000-10-06 2010-04-30 Киова Хакко Кирин Ко., Лтд. Cells producing antibody compositions
US6946292B2 (en) 2000-10-06 2005-09-20 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions with increased antibody dependent cytotoxic activity
EP1333032A4 (en) 2000-10-06 2005-03-16 Kyowa Hakko Kogyo Kk Method of purifying antibody
ATE489395T1 (en) 2000-12-12 2010-12-15 Medimmune Llc MOLECULES WITH LONGER HALF-LIFE, COMPOSITIONS AND THEIR USE
US20040002587A1 (en) 2002-02-20 2004-01-01 Watkins Jeffry D. Fc region variants
US20040132101A1 (en) 2002-09-27 2004-07-08 Xencor Optimized Fc variants and methods for their generation
DE10161767T1 (en) * 2002-07-03 2018-06-07 Honjo Tasuku Immunopotentiating compositions containing an anti-PD-L1 antibody
EP3502133A1 (en) 2002-09-27 2019-06-26 Xencor, Inc. Optimized fc variants and methods for their generation
EP2368578A1 (en) 2003-01-09 2011-09-28 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US20050226867A1 (en) 2003-10-08 2005-10-13 Kyowa Hakko Kogyo Co., Ltd. IL-5R-specific antibody composition
RS52036B (en) * 2004-12-21 2012-04-30 Medimmune Limited Antibodies directed to angiopoietin-2 and uses thereof
PT2397156T (en) * 2005-06-08 2016-12-23 The President And Fellows Of Harvard College Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (pd-1)pathway
TW200815469A (en) * 2006-06-23 2008-04-01 Astrazeneca Ab Compounds
EP2061504A4 (en) * 2006-09-20 2010-01-27 Univ Johns Hopkins Combinatorieal therapy of cancer and infectious diseases with anti-b7-h1 antibodies
CN101663323A (en) * 2006-12-27 2010-03-03 埃默里大学 The composition and the method that are used for the treatment of transmissible disease and tumour
EP2170959B1 (en) * 2007-06-18 2013-10-02 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
WO2009089149A1 (en) * 2008-01-03 2009-07-16 The Johns Hopkins University B7-h1 (cd274) antagonists induce apoptosis of tumor cells
KR101050829B1 (en) * 2008-10-02 2011-07-20 서울대학교산학협력단 Anticancer agents comprising an anti-PD-1 antibody or an anti-PD-L1 antibody
CN108997498A (en) * 2008-12-09 2018-12-14 霍夫曼-拉罗奇有限公司 Anti- PD-L1 antibody and they be used to enhance the purposes of T cell function
DK3279215T3 (en) * 2009-11-24 2020-04-27 Medimmune Ltd TARGETED BINDING AGENTS B7-H1
JP6071725B2 (en) 2013-04-23 2017-02-01 カルソニックカンセイ株式会社 Driving force control device for electric vehicles
US9209965B2 (en) 2014-01-14 2015-12-08 Microsemi Semiconductor Ulc Network interface with clock recovery module on line card
US11392902B2 (en) 2017-06-06 2022-07-19 United Parcel Service Of America, Inc. Systems, methods, apparatuses and computer program products for providing notification of items for pickup and delivery
US11284893B2 (en) 2019-04-02 2022-03-29 Covidien Lp Stapling device with articulating tool assembly

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050226883A1 (en) * 2004-02-06 2005-10-13 Paul Averback Humanized antibody
US20090055944A1 (en) * 2005-07-01 2009-02-26 Medarex, Inc. Human monoclonal antibodies to be programmed death ligand 1 (pd-l1)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
LI ET AL.: "Anti-Programmed Death-1 Synergized with Granulocyte Macrophage Colony- Stimulating Factor-Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors", CLINICAL CANCER RESEARCH, vol. 15, no. 5, March 2009 (2009-03-01), pages 1623 - 1634, XP055166457, DOI: doi:10.1158/1078-0432.CCR-08-1825 *
LIN ET AL.: "The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors", PNAS, vol. 105, no. 8, 26 February 2008 (2008-02-26), USA, pages 3011 - 3016, XP002683218, DOI: doi:10.1073/PNAS.0712278105 *
LIN, D ET AL., PROC. NATL. ACAD. SCI. USA, vol. 105, 2008, pages 3011 - 3016
NOMI ET AL.: "Clinical Significance and Therapeutic Potential of the Programmed Death-1 Pathway in Human Pancreatic Cancer", CLINICAL CANCER RESEARCH, vol. 13, 2007, pages 2151 - 2157, XP002533527, DOI: doi:10.1158/1078-0432.CCR-06-2746 *
STROME ET AL.: "B7-H1 Blockade Augments Adoptive t-Cell Immunotherapy for Squamous Cell Carcinoma", CANCER RESEARCH, vol. 63, 2003, pages 6501 - 6505, XP002487684 *

Cited By (826)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11685792B2 (en) 2008-01-31 2023-06-27 Inserm (Institut National De La Sante Et De La Recherche Medicale) Antibodies against human CD39 and use thereof for inhibiting T regulatory cells activity
US10662253B2 (en) 2008-01-31 2020-05-26 Inserm (Institut National De La Sante Et De La Recherche Medicale) Antibodies against human CD39 and use thereof for inhibiting T regulatory cells activity
US10072087B2 (en) 2009-12-10 2018-09-11 Hoffmann-La Roche Inc. Antibodies against human CSF-1R and uses thereof
US11492383B2 (en) 2011-06-24 2022-11-08 Stephen D. Gillies Light chain immunoglobulin fusion proteins and methods of use thereof
US10646567B2 (en) 2011-08-01 2020-05-12 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
US11884724B2 (en) 2011-11-28 2024-01-30 Merck Patent Gmbh Anti-PD-L1 antibodies and uses thereof
US9624298B2 (en) 2011-11-28 2017-04-18 Merck Patent Gmbh Anti-PD-L1 antibodies and uses thereof
US10759856B2 (en) 2011-11-28 2020-09-01 Merck Patent Gmbh Anti-PD-L1 antibodies and uses thereof
EP3763741A1 (en) 2011-11-28 2021-01-13 Merck Patent GmbH Anti-pd-l1 antibodies and uses thereof
US10487147B2 (en) 2011-11-28 2019-11-26 Merck Patent Gmbh Anti-PD-L1 antibodies and uses thereof
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
US10266594B1 (en) 2012-05-15 2019-04-23 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10577423B2 (en) 2012-05-15 2020-03-03 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US9856320B2 (en) 2012-05-15 2018-01-02 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10323093B2 (en) 2012-05-15 2019-06-18 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
EP3309175A1 (en) 2012-05-15 2018-04-18 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting pd-1/pd-l1 signaling
US10266595B2 (en) 2012-05-15 2019-04-23 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10266596B1 (en) 2012-05-15 2019-04-23 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10323092B2 (en) 2012-05-15 2019-06-18 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10138299B2 (en) 2012-05-15 2018-11-27 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10316090B2 (en) 2012-05-15 2019-06-11 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10584170B2 (en) 2012-05-15 2020-03-10 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US9212224B2 (en) 2012-05-15 2015-12-15 Bristol-Myers Squibb Company Antibodies that bind PD-L1 and uses thereof
US10604575B2 (en) 2012-05-15 2020-03-31 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10072082B2 (en) 2012-05-15 2018-09-11 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10316091B2 (en) 2012-05-15 2019-06-11 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
US10308714B2 (en) 2012-05-15 2019-06-04 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
JP2020073571A (en) * 2012-05-31 2020-05-14 ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. Antigen binding protein that binds pd-l1
JP2015519375A (en) * 2012-05-31 2015-07-09 ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. Antigen binding protein that binds to PD-L1
US11878058B2 (en) 2012-05-31 2024-01-23 Sorrento Therapeutics, Inc. Antigen binding proteins that bind PD-L1
US10058609B2 (en) 2012-05-31 2018-08-28 Sorrento Therapeutics, Inc. Antigen binding proteins that bind PD-L1
CN109467601A (en) * 2012-05-31 2019-03-15 索伦托治疗有限公司 Antigen-binding proteins in conjunction with PD-L1
EP2854843A4 (en) * 2012-05-31 2016-06-01 Sorrento Therapeutics Inc Antigen binding proteins that bind pd-l1
EP3553086A1 (en) * 2012-05-31 2019-10-16 Sorrento Therapeutics Inc. Antigen binding proteins that bind pd-l1
CN109467601B (en) * 2012-05-31 2022-07-08 索伦托药业有限公司 Antigen binding proteins that bind to PD-L1
JP2017197586A (en) * 2012-05-31 2017-11-02 ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. Antigen binding protein that binds pd-l1
US11027012B2 (en) 2012-05-31 2021-06-08 Sorrento Therapeutics, Inc. Antigen binding proteins that bind PD-L1
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
US10548988B2 (en) 2012-07-18 2020-02-04 Birdie Biopharmaceuticals, Inc. Compounds for targeted immunotherapy
US10660971B2 (en) 2012-07-18 2020-05-26 Birdie Biopharmaceuticals, Inc. Compounds for targeted immunotherapy
EP3263601A1 (en) 2012-10-02 2018-01-03 Bristol-Myers Squibb Company Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer
WO2014055648A1 (en) 2012-10-02 2014-04-10 Bristol-Myers Squibb Company Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer
US9828434B2 (en) 2012-10-04 2017-11-28 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-PD-L1 antibodies and methods of use
EP2903641A2 (en) * 2012-10-04 2015-08-12 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-pd-l1 antibodies and methods of use
US10604581B2 (en) 2012-10-04 2020-03-31 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-PD-L1 antibodies and methods of use
US11578372B2 (en) 2012-11-05 2023-02-14 Foundation Medicine, Inc. NTRK1 fusion molecules and uses thereof
EP2926142B1 (en) 2012-11-30 2018-11-07 F.Hoffmann-La Roche Ag Identification of patients in need of pd-l1 inhibitor cotherapy
US11226339B2 (en) 2012-12-11 2022-01-18 Albert Einstein College Of Medicine Methods for high throughput receptor:ligand identification
KR102208505B1 (en) * 2012-12-11 2021-01-27 앨버트 아인슈타인 컬리지 오브 메디신 Methods for high throughput receptor:ligand identification
KR20150094674A (en) * 2012-12-11 2015-08-19 알버트 아인슈타인 컬리지 오브 메디신 오브 예쉬바 유니버시티 Methods for high throughput receptor:ligand identification
CN113321731A (en) * 2012-12-21 2021-08-31 默沙东公司 Antibodies that bind human programmed death ligand 1(PD-L1)
JP2019193665A (en) * 2012-12-21 2019-11-07 メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. Antibodies that bind to human programmed death ligand 1 (pd-l1)
JP2021097705A (en) * 2012-12-21 2021-07-01 メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. Antibodies that bind to human programmed death ligand 1 (PD-L1)
JP2016504336A (en) * 2012-12-21 2016-02-12 メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. Antibody binding to human programmed death ligand 1 (PD-L1)
EP2943507B1 (en) 2013-01-10 2020-02-26 Genmab A/S Inert format
US20150344577A1 (en) * 2013-01-11 2015-12-03 Dingfu Biotarget Co., Ltd Agents for treating tumors, use and method thereof
US11771698B2 (en) 2013-01-18 2023-10-03 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
US11458195B2 (en) 2013-02-22 2022-10-04 Curevac Ag Combination of vaccination and inhibition of the PD-1 pathway
EP3292873B1 (en) 2013-02-22 2019-05-01 CureVac AG Combination of vaccination and inhibition of the pd-1 pathway
US10167336B2 (en) 2013-03-14 2019-01-01 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
US11299544B2 (en) 2013-03-15 2022-04-12 Genentech, Inc. Biomarkers and methods of treating PD-1 and PD-L1 related conditions
US9192667B2 (en) 2013-04-22 2015-11-24 Hoffmann-La Roche Inc. Method of treating cancer by administering CSF-1R antibodies and a TLR9 agonist
WO2015016718A1 (en) 2013-08-02 2015-02-05 Bionovion Holding B.V. Combining cd27 agonists and immune checkpoint inhibition for immune stimulation
EP3366289A1 (en) 2013-09-06 2018-08-29 Aurigene Discovery Technologies Limited Cyclic peptidomimetic compounds as immunomodulators
US11512060B2 (en) 2013-09-06 2022-11-29 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015033303A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Cyclic peptidomimetic compounds as immunomodulators
EP3363790A1 (en) 2013-09-06 2018-08-22 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10173989B2 (en) 2013-09-06 2019-01-08 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015033299A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US9771338B2 (en) 2013-09-06 2017-09-26 Auirgene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10160736B2 (en) 2013-09-06 2018-12-25 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
US10961205B2 (en) 2013-09-06 2021-03-30 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10590093B2 (en) 2013-09-06 2020-03-17 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US12037321B2 (en) 2013-09-06 2024-07-16 Aurigene Oncology Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10106581B2 (en) 2013-09-06 2018-10-23 Aurigene Discovery Technologies Limited Cyclic peptidomimetic compounds as immunomodulators
WO2015033301A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
EP3385257A1 (en) 2013-09-06 2018-10-10 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
US9776978B2 (en) 2013-09-06 2017-10-03 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
CN105873606A (en) * 2013-09-11 2016-08-17 米迪缪尼有限公司 Anti-b7-h1 antibodies for treating tumors
IL274462A (en) * 2013-09-11 2020-06-30 Medimmune Ltd Anti-b7-h1 antibodies for treating tumors
WO2015036499A1 (en) * 2013-09-11 2015-03-19 Medimmune Limited Anti-b7-h1 antibodies for treating tumors
CN105873606B (en) * 2013-09-11 2020-12-29 米迪缪尼有限公司 anti-B7-H1 antibodies for the treatment of tumors
US10336823B2 (en) 2013-09-11 2019-07-02 Medimmune Limited Anti-B7-H1 antibodies for treating tumors
US11827706B2 (en) 2013-09-11 2023-11-28 Medimmune Limited Anti-B7-H1 antibodies for treating tumors
EP3656398A1 (en) 2013-09-11 2020-05-27 MedImmune Limited Anti-b7-h1 antibodies for treating tumors
AU2020223728B2 (en) * 2013-09-11 2024-03-07 Medimmune Limited Anti-b7-h1 antibodies for treating tumors
US10829557B2 (en) 2013-09-11 2020-11-10 Medimmune Limited Anti-B7-H1 antibodies for treating tumors
RU2701327C2 (en) * 2013-09-11 2019-09-25 Медиммьюн Лимитед Antibodies to b7-h1 for treating tumours
US11512133B2 (en) 2013-09-12 2022-11-29 Hoffmann-La Roche Inc. Methods for treating colon cancer or inhibiting cell proliferation by administering a combination of antibodies against human CSF-1R and antibodies against human PD-L1
WO2015036511A1 (en) * 2013-09-12 2015-03-19 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and antibodies against human pd-l1
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
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
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
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
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
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
US11708412B2 (en) 2013-09-26 2023-07-25 Novartis Ag Methods for treating hematologic cancers
US10259875B2 (en) 2013-10-01 2019-04-16 Mayo Foundation For Medical Education And Research Methods for treating cancer in patients with elevated levels of BIM
US11136393B2 (en) 2013-10-01 2021-10-05 Mayo Foundation For Medical Education And Research Methods for treating cancer in patients with elevated levels of Bim
EP3647324A1 (en) 2013-12-17 2020-05-06 F. Hoffmann-La Roche AG Methods of treating cancers using pd-1 axis binding antagonists and taxanes
US20170008971A1 (en) * 2013-12-17 2017-01-12 Genentech, Inc. Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
EP3680254A1 (en) 2013-12-17 2020-07-15 F. Hoffmann-La Roche AG Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
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
EP3527587A1 (en) 2013-12-17 2019-08-21 F. Hoffmann-La Roche AG Combination therapy comprising ox40 binding agonists and pd-l1 binding antagonists
DE202014010421U1 (en) 2013-12-17 2015-11-12 Kymab Limited Human goals
WO2015095418A1 (en) 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
WO2015095423A2 (en) 2013-12-17 2015-06-25 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
US10548985B2 (en) 2014-01-10 2020-02-04 Birdie Biopharmaceuticals, Inc. Compounds and compositions for treating EGFR expressing tumors
US10328158B2 (en) 2014-01-10 2019-06-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US10744206B2 (en) 2014-01-10 2020-08-18 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US11633495B2 (en) 2014-01-10 2023-04-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US11786604B2 (en) 2014-01-10 2023-10-17 Birdie Biopharmaceuticals, Inc. Compounds and compositions for treating HER2 positive tumors
US11633494B2 (en) 2014-01-10 2023-04-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US10780180B2 (en) 2014-01-10 2020-09-22 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US10737113B2 (en) 2014-01-23 2020-08-11 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-1
EA034695B1 (en) * 2014-01-23 2020-03-06 Регенерон Фармасьютикалс, Инк. Human antibodies to pd-l1
US9938345B2 (en) 2014-01-23 2018-04-10 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-L1
EP3473648A1 (en) 2014-01-23 2019-04-24 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
US11117970B2 (en) 2014-01-23 2021-09-14 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-L1
AU2015209238B2 (en) * 2014-01-23 2019-09-12 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-L1
US9987500B2 (en) 2014-01-23 2018-06-05 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-1
WO2015112805A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
TWI680138B (en) * 2014-01-23 2019-12-21 美商再生元醫藥公司 Human antibodies to pd-l1
US9683048B2 (en) 2014-01-24 2017-06-20 Novartis Ag Antibody molecules to PD-1 and uses thereof
US9815898B2 (en) 2014-01-24 2017-11-14 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
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
US9884913B2 (en) 2014-01-31 2018-02-06 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US10472419B2 (en) 2014-01-31 2019-11-12 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
US11370819B2 (en) 2014-02-10 2022-06-28 Merck Patent Gmbh Targeted TGFβ inhibition
US11773175B2 (en) 2014-03-04 2023-10-03 Kymab Limited Antibodies, uses and methods
US11753479B2 (en) 2014-03-04 2023-09-12 Kymab Limited Nucleic acids encoding anti-OX40L antibodies
US11110157B2 (en) 2014-03-12 2021-09-07 Curevac Ag Combination of vaccination and OX40 agonists
US10730951B2 (en) 2014-03-31 2020-08-04 Genentech, Inc. Anti-OX40 antibodies and methods of use
US9975957B2 (en) 2014-03-31 2018-05-22 Genentech, Inc. Anti-OX40 antibodies and methods of use
US10302653B2 (en) 2014-05-22 2019-05-28 Mayo Foundation For Medical Education And Research Distinguishing antagonistic and agonistic anti B7-H1 antibodies
US20160031990A1 (en) * 2014-05-29 2016-02-04 Medlmmune, Llc Antagonists of pdl-1 and pd-1 for the treatment of hpv-negative cancers
EP3610924A1 (en) 2014-06-06 2020-02-19 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses 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
EP3998079A1 (en) 2014-06-06 2022-05-18 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
WO2015195163A1 (en) * 2014-06-20 2015-12-23 R-Pharm Overseas, Inc. Pd-l1 antagonist fully human antibody
US11279761B2 (en) 2014-07-09 2022-03-22 Birdie Biopharmaceuticals, Inc. Anti-PD-L1 combinations for treating tumors
WO2016004876A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Anti-pd-l1 combinations for treating tumors
EP4001311A1 (en) 2014-07-09 2022-05-25 Birdie Biopharmaceuticals Inc. Anti-pd-l1 combinations for treating tumors
US10689445B2 (en) 2014-07-11 2020-06-23 Ventana Medical Systems, Inc. Anti-PD-L1 antibodies and diagnostic uses thereof
WO2016007235A1 (en) 2014-07-11 2016-01-14 Genentech, Inc. Anti-pd-l1 antibodies and diagnostic uses thereof
EP3309174A1 (en) 2014-07-11 2018-04-18 Genentech, Inc. Anti-pd-l1 antibodies and diagnostic uses thereof
US11530269B2 (en) 2014-07-11 2022-12-20 Ventana Medical Systems, Inc. Anti-PD-L1 antibodies and diagnostic uses thereof
EP3563870A1 (en) 2014-07-15 2019-11-06 F. Hoffmann-La Roche AG Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors
US10946093B2 (en) 2014-07-15 2021-03-16 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
WO2016011160A1 (en) 2014-07-15 2016-01-21 Genentech, Inc. Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors
US10517875B2 (en) 2014-07-23 2019-12-31 Mayo Foundation for Medical Engineering and Research Targeting DNA-PKcs and B7-H1 to treat cancer
US11504376B2 (en) 2014-07-23 2022-11-22 Mayo Foundation For Medical Education And Research Targeting DNA-PKCS and B7-H1 to treat cancer
WO2016030455A1 (en) 2014-08-28 2016-03-03 Medimmune Limited Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small lung cancer
EP3763742A1 (en) 2014-09-01 2021-01-13 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
EP4148069A1 (en) 2014-09-01 2023-03-15 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
US11130812B2 (en) 2014-09-01 2021-09-28 Birdie Biopharmaceuticals, Inc. Anti PD-L1 conjugates for treating tumors
WO2016034718A1 (en) * 2014-09-05 2016-03-10 Medimmune Limited Methods for identifying patients responsive to anti-pd-l1 antibody therapy using markers (cxcl9, krt8.trim29, and ifngamma)
RU2817281C2 (en) * 2014-09-11 2024-04-12 Медиммьюн Лимитед Antibodies to b7-h1 for treating tumours
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies
EP4368205A1 (en) 2014-09-16 2024-05-15 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
EP3799885A1 (en) 2014-09-16 2021-04-07 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
EP3689910A2 (en) 2014-09-23 2020-08-05 F. Hoffmann-La Roche AG Method of using anti-cd79b immunoconjugates
EP3736294A2 (en) 2014-10-10 2020-11-11 Innate Pharma Cd73 blockade
US10851165B2 (en) 2014-10-14 2020-12-01 Novartis Ag Antibody molecules to PD-L1 and methods of treating cancer
US9988452B2 (en) 2014-10-14 2018-06-05 Novartis Ag Antibody molecules to PD-L1 and uses thereof
EP3550019A1 (en) 2014-10-24 2019-10-09 Astrazeneca AB Combination
WO2016081384A1 (en) 2014-11-17 2016-05-26 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
EP4141032A1 (en) 2014-11-20 2023-03-01 F. Hoffmann-La Roche AG Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists
EP3789402A1 (en) 2014-11-20 2021-03-10 F. Hoffmann-La Roche AG Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists
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
WO2016090300A1 (en) 2014-12-05 2016-06-09 Genentech, Inc. Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists
EP3808775A1 (en) * 2014-12-09 2021-04-21 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized cluster of differentiation 274 gene
US9913461B2 (en) 2014-12-09 2018-03-13 Regeneron Pharmaceuticals, Inc. Genetically modified mouse whose genome comprises a humanized CD274 gene
US12089575B2 (en) 2014-12-09 2024-09-17 Regeneron Pharmaceuticals, Inc. Genetically modified mouse that expresses humanized PD1 and PD-L1 proteins
US10881086B2 (en) 2014-12-09 2021-01-05 Regeneron Pharmaceuticals, Inc. Genetically modified mouse whose genome comprises a humanized CD274 gene
WO2016094481A1 (en) * 2014-12-09 2016-06-16 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized cluster of differentiation 274 gene
CN113412818A (en) * 2014-12-09 2021-09-21 瑞泽恩制药公司 Non-human animal having humanized cluster of differentiation 274 gene
EP4249066A2 (en) 2014-12-23 2023-09-27 Bristol-Myers Squibb Company Antibodies to tigit
US11534489B2 (en) 2015-01-09 2022-12-27 Agency For Science, Technology And Research Anti-PD-L1 antibodies
US9789183B1 (en) 2015-01-09 2017-10-17 Agency For Science, Technology And Research Anti-PD-L1 antibodies
WO2016111645A1 (en) * 2015-01-09 2016-07-14 Agency For Science, Technology And Research Anti-pd-l1 antibodies
US10517949B2 (en) 2015-01-09 2019-12-31 Agency For Science, Technology And Research Anti-PD-L1 antibodies
WO2016127052A1 (en) 2015-02-05 2016-08-11 Bristol-Myers Squibb Company Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy
US10357491B2 (en) 2015-03-06 2019-07-23 Beyondspring Pharmaceuticals, Inc. Method of treating a brain tumor
US10238650B2 (en) 2015-03-06 2019-03-26 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
US11045467B2 (en) 2015-03-06 2021-06-29 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
US10668063B2 (en) 2015-03-06 2020-06-02 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
US10076518B2 (en) 2015-03-06 2018-09-18 Beyondspring Pharmaceuticals, Inc. Method of treating a brain tumor
US11918574B2 (en) 2015-03-06 2024-03-05 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
US10781189B2 (en) 2015-03-10 2020-09-22 Aurigene Discovery Technologies Limited 1,2,4-Oxadiazole and thiadiazole compounds as immunomodulators
WO2016142833A1 (en) 2015-03-10 2016-09-15 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators
US11465976B2 (en) 2015-03-10 2022-10-11 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators
EP4023645A1 (en) 2015-03-10 2022-07-06 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators
US10669339B2 (en) 2015-03-13 2020-06-02 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
AU2016233495B2 (en) * 2015-03-13 2022-02-24 Cytomx Therapeutics, Inc Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
WO2016149201A3 (en) * 2015-03-13 2016-11-24 Cytomx Therapeutics, Inc. Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof
US11174316B2 (en) 2015-03-13 2021-11-16 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
US10336824B2 (en) 2015-03-13 2019-07-02 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of thereof
WO2016146259A1 (en) 2015-03-16 2016-09-22 Amal Therapeutics Sa A novel complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for treatment of glioblastoma
EP3693009A1 (en) 2015-03-16 2020-08-12 Amal Therapeutics SA A novel complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for treatment of colorectal cancer
WO2016146261A1 (en) 2015-03-16 2016-09-22 Amal Therapeutics Sa Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine
US11933786B2 (en) 2015-03-30 2024-03-19 Stcube, Inc. Antibodies specific to glycosylated PD-L1 and methods of use thereof
EP3277320A4 (en) * 2015-03-30 2018-08-01 Stcube, Inc. Antibodies specific to glycosylated pd-l1 and methods of use thereof
US10836827B2 (en) 2015-03-30 2020-11-17 Stcube, Inc. Antibodies specific to glycosylated PD-L1 and methods of use thereof
US11491204B2 (en) 2015-04-07 2022-11-08 Cytlimic Inc. Composition comprising poly I:C and LAG-3-IGG fusion protein
WO2016166348A1 (en) * 2015-04-17 2016-10-20 Elsalys Biotech Anti-tyro3 antibodies and uses thereof
CN108064245A (en) * 2015-04-17 2018-05-22 埃尔萨里斯生物技术公司 Anti- Tyro3 antibody and application thereof
CN104830788A (en) * 2015-05-05 2015-08-12 杨光华 DC cell based on HBV-HCV antigen, targeting immune cell population, preparation method and applications thereof
EP3783029A1 (en) 2015-05-12 2021-02-24 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
WO2016181349A1 (en) 2015-05-14 2016-11-17 Pfizer Inc. Combinations comprising a pyrrolidine-2,5-dione ido1 inhibitor and an anti-body
US10945994B2 (en) 2015-05-14 2021-03-16 Pfizer Inc. Combinations comprising a pyrrolidine-2,5-dione IDO1 inhibitor and an anti-body
WO2016196381A1 (en) 2015-05-29 2016-12-08 Genentech, Inc. Pd-l1 promoter methylation in cancer
EP3763827A1 (en) 2015-05-29 2021-01-13 F. Hoffmann-La Roche AG Pd-l1 promoter methylation in cancer
WO2016196228A1 (en) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Antibodies against ox40 and uses thereof
EP4335931A2 (en) 2015-05-29 2024-03-13 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
US11254987B2 (en) 2015-05-29 2022-02-22 Genentech, Inc. PD-L1 promoter methylation in cancer
WO2016196298A1 (en) 2015-05-29 2016-12-08 Genentech, Inc. Therapeutic and diagnolstic methods for cancer
EP3708681A1 (en) 2015-05-29 2020-09-16 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
WO2016196218A1 (en) 2015-05-31 2016-12-08 Curegenix Corporation Combination compositions for immunotherapy
WO2016200835A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
WO2016197204A1 (en) 2015-06-11 2016-12-15 Bionomics Limited Pharmaceutical combination and uses thereof
WO2016201425A1 (en) 2015-06-12 2016-12-15 Bristol-Myers Squibb Company Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways
WO2016205320A1 (en) 2015-06-17 2016-12-22 Genentech, Inc. Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes
WO2017004016A1 (en) 2015-06-29 2017-01-05 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
US10155748B2 (en) 2015-07-13 2018-12-18 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
US11254657B2 (en) 2015-07-13 2022-02-22 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
US12024501B2 (en) 2015-07-13 2024-07-02 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
US10550104B2 (en) 2015-07-13 2020-02-04 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
EP3878465A1 (en) 2015-07-29 2021-09-15 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
EP3964528A1 (en) 2015-07-29 2022-03-09 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
WO2017019897A1 (en) 2015-07-29 2017-02-02 Novartis Ag Combination therapies comprising antibody molecules to tim-3
US11225522B2 (en) 2015-07-31 2022-01-18 Suzhou Alphamab Co., Ltd. Single domain antibody and derivative proteins thereof against programmed death-ligand (PDL1)
EP3330290A4 (en) * 2015-07-31 2019-08-28 Suzhou Alphamab Co., Ltd Single domain antibody for programmed death-ligand (pd-l1) and derived protein thereof
RU2715595C2 (en) * 2015-07-31 2020-03-02 3Д Медисинес (Бейджинг) Ко., Лтд. Single-domain antibody and derivatives thereof to ligand-1 protein of programmed cell death (pdli)
EP3348571A4 (en) * 2015-07-31 2019-04-10 Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Single domain antibody for programmed death-ligand (pd-l1) and derived protein thereof
AU2016302951B2 (en) * 2015-07-31 2019-10-10 3D Medicines (Beijing) Co., Ltd. Single domain antibody for programmed death-ligand (PD-L1) and derived protein thereof
EP3332006B1 (en) * 2015-08-06 2023-10-11 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
WO2017020858A1 (en) 2015-08-06 2017-02-09 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
US10981995B2 (en) 2015-08-06 2021-04-20 Wuxi Biologies Ireland Limited Anti-PD-L1 antibodies
US10214586B2 (en) 2015-08-24 2019-02-26 Eli Lilly And Company PD-L1 antibodies
EA039736B1 (en) * 2015-09-15 2022-03-04 Сайтомкс Терапьютикс, Инк. Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof
WO2017055484A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for determining the metabolic status of lymphomas
WO2017058780A1 (en) 2015-09-30 2017-04-06 Merck Patent Gmbh Combination of a pd-1 axis binding antagonist and an alk inhibitor for treating alk-negative cancer
EP3360893A4 (en) * 2015-10-10 2019-01-23 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences High-affinity and soluble pdl-1 molecule
WO2017064043A1 (en) 2015-10-12 2017-04-20 Innate Pharma Cd73 blocking agents
US10875923B2 (en) 2015-10-30 2020-12-29 Mayo Foundation For Medical Education And Research Antibodies to B7-H1
WO2017075045A3 (en) * 2015-10-30 2017-06-08 Mayo Foundation For Medical Education And Research Antibodies to b7-h1
WO2017077382A1 (en) 2015-11-06 2017-05-11 Orionis Biosciences Nv Bi-functional chimeric proteins and uses thereof
WO2017087280A1 (en) 2015-11-16 2017-05-26 Genentech, Inc. Methods of treating her2-positive cancer
AU2016357901B2 (en) * 2015-11-17 2023-05-25 Jiangsu Hengrui Medicine Co., Ltd. Pd-l1 antibody, antigen-binding fragment thereof and medical application thereof
TWI718206B (en) * 2015-11-17 2021-02-11 大陸商江蘇恆瑞醫藥股份有限公司 Pd-l1 antibody, antigen-binding fragments and pharmaceutical use thereof
EP3378871A4 (en) * 2015-11-17 2019-08-07 Suzhou Suncadia Biopharmaceuticals Co., Ltd. Pd-l1 antibody, antigen fragment binding thereof and pharmaceutical use thereof
US11780923B2 (en) 2015-11-17 2023-10-10 Suzhou Suncadia Biopharmaceuticals Co., Ltd. PD-L1 antibody, antigen-binding fragment thereof and medical application 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
WO2017087851A1 (en) 2015-11-19 2017-05-26 Genentech, Inc. Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors
US11981736B2 (en) 2015-12-02 2024-05-14 St Cube Inc. Antibodies specific to glycosylated PD-1 and methods of use thereof
US10858432B2 (en) 2015-12-02 2020-12-08 Stcube, Inc. Antibodies specific to glycosylated PD-1 and methods of use thereof
EP3178848A1 (en) 2015-12-09 2017-06-14 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies
EP4026848A1 (en) 2015-12-09 2022-07-13 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing the cytokine release syndrome
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
US12054557B2 (en) 2015-12-22 2024-08-06 Regeneron Pharmaceuticals, Inc. Combination of anti-PD-1 antibodies and bispecific anti-CD20/anti-CD3 antibodies to treat cancer
WO2017112741A1 (en) 2015-12-22 2017-06-29 Novartis Ag Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy
WO2017118634A1 (en) 2016-01-04 2017-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma
US11220552B2 (en) 2016-01-07 2022-01-11 Birdie Biopharmaceuticals, Inc. Anti-CD20 combinations for treating tumors
US11136397B2 (en) 2016-01-07 2021-10-05 Birdie Pharmaceuticals, Inc. Anti-EGFR combinations for treating tumors
US11046781B2 (en) 2016-01-07 2021-06-29 Birdie Biopharmaceuticals, Inc. Anti-HER2 combinations for treating tumors
US11702476B2 (en) 2016-01-07 2023-07-18 Birdie Biopharmaceuticals, Inc. Anti-EGFR combinations for treating tumors
EP3862365A1 (en) 2016-01-08 2021-08-11 F. Hoffmann-La Roche AG Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies
US10596257B2 (en) 2016-01-08 2020-03-24 Hoffmann-La Roche Inc. Methods of treating CEA-positive cancers using PD-1 axis binding antagonists and anti-CEA/anti-CD3 bispecific antibodies
WO2017125532A1 (en) 2016-01-21 2017-07-27 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
EP3868787A1 (en) 2016-01-21 2021-08-25 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
EP4421094A2 (en) 2016-02-05 2024-08-28 Orionis Biosciences BV Targeted therapeutic agents and uses thereof
WO2017134302A2 (en) 2016-02-05 2017-08-10 Orionis Biosciences Nv Targeted therapeutic agents and uses thereof
EP4059957A1 (en) 2016-02-05 2022-09-21 Orionis Biosciences BV Bispecific signaling agents and uses thereof
EP3998281A1 (en) 2016-02-05 2022-05-18 Orionis Biosciences BV Cd8 binding agents
WO2017134305A1 (en) 2016-02-05 2017-08-10 Orionis Biosciences Nv Bispecific signaling agents and uses thereof
EP3909978A1 (en) 2016-02-05 2021-11-17 Orionis Biosciences BV Clec9a binding agents and use thereof
US10912748B2 (en) 2016-02-08 2021-02-09 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
US11857522B2 (en) 2016-02-08 2024-01-02 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
CN108699153A (en) * 2016-02-25 2018-10-23 细胞医学瑞士公司 The binding members of PD-L1
US11434294B2 (en) 2016-02-25 2022-09-06 Cell Medica, Inc. Binding members to PD-L1
WO2017144681A1 (en) 2016-02-25 2017-08-31 Cell Medica Switzerland Ag Binding members to pd-l1
EP4086285A1 (en) 2016-02-25 2022-11-09 Cell Medica Switzerland AG Binding members to pd-l1
WO2017151502A1 (en) 2016-02-29 2017-09-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP4155415A1 (en) 2016-02-29 2023-03-29 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP3804620A1 (en) 2016-03-01 2021-04-14 North Carolina State University Enhanced cancer immunotherapy by microneedle patch-assisted delivery
US11896800B2 (en) 2016-03-01 2024-02-13 North Carolina State University Enhanced cancer immunotherapy by microneedle patch-assisted delivery
EP3309177A4 (en) * 2016-03-04 2018-10-10 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Pdl-1 antibody, pharmaceutical composition thereof, and uses thereof
US10465014B2 (en) 2016-03-04 2019-11-05 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. PDL-1 antibody, pharmaceutical composition thereof, and uses thereof
US11136413B2 (en) 2016-03-04 2021-10-05 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. PDL-1 antibody, pharmaceutical composition thereof, and uses thereof
WO2017152085A1 (en) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Combination therapy with anti-cd73 antibodies
WO2017153433A1 (en) 2016-03-08 2017-09-14 Innate Pharma Siglec neutralizing antibodies
US11110168B2 (en) 2016-03-15 2021-09-07 North Carolina State University Nanoparticles, controlled-release dosage forms, and methods for delivering an immunotherapeutic agent
WO2017159699A1 (en) 2016-03-15 2017-09-21 Chugai Seiyaku Kabushiki Kaisha Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies
EP4112641A1 (en) 2016-03-15 2023-01-04 Chugai Seiyaku Kabushiki Kaisha Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies
WO2017157964A1 (en) 2016-03-16 2017-09-21 Amal Therapeutics Sa Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine
US11287428B2 (en) 2016-03-16 2022-03-29 H. Lee Moffitt Cancer Center And Research Institute, Inc. PD1 and PDL-1 expression during progression from myelodysplastic syndrome to acute myelogenous leukemia
US11753473B2 (en) 2016-03-23 2023-09-12 Suzhou Transcenta Therapeutics Co., Ltd. Anti-PD-L1 antibodies
EP3433277A4 (en) * 2016-03-23 2020-06-17 Mabspace Biosciences (Suzhou) Co., Ltd Novel anti-pd-l1 antibodies
US10822416B2 (en) 2016-03-23 2020-11-03 Mabspace Biosciences (Suzhou) Co., Ltd Anti-PD-L1 antibodies
US11660352B2 (en) 2016-03-29 2023-05-30 Stcube, Inc. Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof
US12059474B2 (en) 2016-03-29 2024-08-13 Stcube & Co., Inc. Methods for selecting antibodies that specifically bind glycosylated immune checkpoint proteins
WO2017167921A1 (en) 2016-03-30 2017-10-05 Centre Léon-Bérard Lymphocytes expressing cd73 in cancerous patient dictates therapy
WO2017175156A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
EP4032885A1 (en) 2016-04-07 2022-07-27 GlaxoSmithKline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017175147A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017181111A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017181079A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017184619A2 (en) 2016-04-18 2017-10-26 Celldex Therapeutics, Inc. Agonistic antibodies that bind human cd40 and uses thereof
US11505600B2 (en) 2016-05-13 2022-11-22 Regeneron Pharmaceuticals, Inc. Methods of treating skin cancer by administering a PD-1 inhibitor
WO2017194783A1 (en) 2016-05-13 2017-11-16 Orionis Biosciences Nv Targeted mutant interferon-beta and uses thereof
WO2017194782A2 (en) 2016-05-13 2017-11-16 Orionis Biosciences Nv Therapeutic targeting of non-cellular structures
US10457725B2 (en) 2016-05-13 2019-10-29 Regeneron Pharmaceuticals, Inc. Methods of treating skin cancer by administering a PD-1 inhibitor
US11339201B2 (en) 2016-05-18 2022-05-24 Albert Einstein College Of Medicine Variant PD-L1 polypeptides, T-cell modulatory multimeric polypeptides, and methods of use thereof
US11505591B2 (en) 2016-05-18 2022-11-22 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
WO2017200969A1 (en) 2016-05-20 2017-11-23 Eli Lilly And Company Combination therapy with notch and pd-1 or pd-l1 inhibitors
US10688104B2 (en) 2016-05-20 2020-06-23 Eli Lilly And Company Combination therapy with Notch and PD-1 or PD-L1 inhibitors
US11826317B2 (en) 2016-05-20 2023-11-28 Eli Lilly And Company Combination therapy with notch and PD-1 or PD-L1 inhibitors
WO2017210335A1 (en) 2016-06-01 2017-12-07 Bristol-Myers Squibb Company Imaging methods using 18f-radiolabeled biologics
EP3252078A1 (en) 2016-06-02 2017-12-06 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
US11229642B2 (en) 2016-06-06 2022-01-25 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing neutropenia
WO2017220990A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 antibodies
US10604576B2 (en) 2016-06-20 2020-03-31 Kymab Limited Antibodies and immunocytokines
WO2017220989A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 and il-2 cytokines
WO2017220988A1 (en) 2016-06-20 2017-12-28 Kymab Limited Multispecific antibodies for immuno-oncology
US11965026B2 (en) 2016-06-20 2024-04-23 Kymab Limited Anti-PD-L1 and IL-2 cytokines
US9957323B2 (en) 2016-06-20 2018-05-01 Kymab Limited Anti-ICOS antibodies
US11834505B2 (en) 2016-06-29 2023-12-05 Checkpoint Therapeutics, Inc. PD-L1-specific antibodies and methods of using the same
EP3478723A4 (en) * 2016-06-29 2020-07-29 Checkpoint Therapeutics, Inc. Pd-l1-specific antibodies and methods of using the same
WO2018013818A2 (en) 2016-07-14 2018-01-18 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
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
US11746152B2 (en) 2016-07-20 2023-09-05 Stcube, Inc. Methods of cancer treatment and therapy using a combination of antibodies that bind glycosylated PD-L1
US12030946B2 (en) 2016-08-08 2024-07-09 Hoffmann-La Roche Inc. Therapeutic and diagnostic methods for cancer
WO2018029124A1 (en) 2016-08-08 2018-02-15 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
US11858996B2 (en) 2016-08-09 2024-01-02 Kymab Limited Anti-ICOS antibodies
WO2018029474A2 (en) 2016-08-09 2018-02-15 Kymab Limited Anti-icos antibodies
WO2018031865A1 (en) 2016-08-12 2018-02-15 Genentech, Inc. Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a vegf inhibitor
US11542335B2 (en) 2016-08-25 2023-01-03 Hoffmann-La Roche Inc. Method of treating cancer in a patient by administering an antibody which binds colony stimulating factor-1 receptor (CSF-1R)
WO2018049474A1 (en) 2016-09-16 2018-03-22 Bionomics Limited Antibody and checkpoint inhibitor combination therapy
WO2018055060A1 (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
US11338027B2 (en) 2016-09-21 2022-05-24 Amal Therapeutics Sa Fusion comprising a cell penetrating peptide, a multi epitope and a TLR peptide agonist for treatment of cancer
US11513122B2 (en) 2016-09-26 2022-11-29 Hoffmann-La Roche Inc. Predicting response to PD-1 axis inhibitors
WO2018055145A1 (en) 2016-09-26 2018-03-29 F. Hoffmann-La Roche Ag Predicting response to pd-1 axis inhibitors
WO2018064299A1 (en) 2016-09-29 2018-04-05 Genentech, Inc. Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a taxane
WO2018068028A1 (en) 2016-10-06 2018-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2018065623A2 (en) 2016-10-07 2018-04-12 Enterome Immunogenic compounds for cancer therapy
WO2018065628A2 (en) 2016-10-07 2018-04-12 Enterome Microbiota sequence variants of tumor-related antigenic epitopes
WO2018065625A2 (en) 2016-10-07 2018-04-12 Enterome Immunogenic compounds for cancer therapy
US11759518B2 (en) 2016-10-11 2023-09-19 Nec Corporation Medicine for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein
US11291718B2 (en) 2016-10-11 2022-04-05 Cytlimic Inc. Method for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein
WO2018077893A1 (en) 2016-10-24 2018-05-03 Orionis Biosciences Nv Targeted mutant interferon-gamma and uses thereof
WO2018081621A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Methods of treating urothelial carcinoma using an anti-pd-1 antibody
US11618786B2 (en) 2016-10-30 2023-04-04 Shanghai Henlius Biotech Inc. Anti-PD-L1 antibodies and variants
CN109963589B (en) * 2016-10-30 2023-05-05 上海复宏汉霖生物技术股份有限公司 anti-PD-L1 antibodies and variants
US11274155B2 (en) 2016-10-30 2022-03-15 Shanghai Henlius Biotech Inc. Anti-PD-L1 antibodies and variants
EP3532100A4 (en) * 2016-10-30 2020-11-25 Shanghai Henlius Biotech, Inc. Anti-pd-l1 antibodies and variants
AU2017348475B2 (en) * 2016-10-30 2024-02-08 Shanghai Henlius Biotech, Inc. Anti-PD-L1 antibodies and variants
CN109963589A (en) * 2016-10-30 2019-07-02 上海复宏汉霖生物技术股份有限公司 Anti- PD-L1 antibody and variant
WO2018085555A1 (en) 2016-11-03 2018-05-11 Bristol-Myers Squibb Company Activatable anti-ctla-4 antibodies and uses thereof
US11117968B2 (en) 2016-11-03 2021-09-14 Bristol-Myers Squibb Company Activatable anti-CTLA-4 antibodies and uses thereof
US11779604B2 (en) 2016-11-03 2023-10-10 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses and methods
WO2018093821A1 (en) 2016-11-15 2018-05-24 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
WO2018099978A1 (en) 2016-11-29 2018-06-07 Horst Lindhofer Combination of t-cell redirecting multifunctional antibodies with immune checkpoint modulators and uses thereof
WO2018099539A1 (en) 2016-11-29 2018-06-07 Horst Lindhofer Combination of t-cell redirecting multifunctional antibodies with immune checkpoint modulators and uses thereof
WO2018110515A1 (en) 2016-12-12 2018-06-21 第一三共株式会社 Combination of antibody-drug conjugate and immune checkpoint inhibitor
US11273155B2 (en) 2016-12-12 2022-03-15 Daiichi Sankyo Company, Limited Combination of antibody-drug conjugate and immune checkpoint inhibitor
KR20190095280A (en) 2016-12-12 2019-08-14 다이이찌 산쿄 가부시키가이샤 Combination of Antibody-Drug Conjugates and Immune Checkpoint Inhibitors
WO2018111890A1 (en) 2016-12-12 2018-06-21 Genentech, Inc. Methods of treating cancer using anti-pd-l1 antibodies and antiandrogens
US11987610B2 (en) 2016-12-22 2024-05-21 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11739133B2 (en) 2016-12-22 2023-08-29 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11377478B2 (en) 2016-12-22 2022-07-05 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11401314B2 (en) 2016-12-22 2022-08-02 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11905320B2 (en) 2016-12-22 2024-02-20 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11851467B2 (en) 2016-12-22 2023-12-26 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11498968B2 (en) 2016-12-22 2022-11-15 Hoffmann-La Roche Inc. Treatment of tumors with an anti-CSF-1R antibody in combination with an anti-PD-L1 antibody after failure of anti-PD-L1/PD1 treatment
US11530248B2 (en) 2016-12-22 2022-12-20 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11117945B2 (en) 2016-12-22 2021-09-14 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11505588B2 (en) 2016-12-22 2022-11-22 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US10927158B2 (en) 2016-12-22 2021-02-23 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11708400B2 (en) 2016-12-22 2023-07-25 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11370821B2 (en) 2016-12-22 2022-06-28 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
WO2018127570A1 (en) 2017-01-05 2018-07-12 Netris Pharma Combined treatment with netrin-1 interfering drug and immune checkpoint inhibitors drugs
US11633393B2 (en) 2017-01-06 2023-04-25 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
US11851471B2 (en) 2017-01-09 2023-12-26 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
WO2018129497A1 (en) 2017-01-09 2018-07-12 Bioxcel Therapeutics, Inc. Predictive and diagnostic methods for prostate cancer
WO2018138591A1 (en) 2017-01-24 2018-08-02 Pfizer Inc. Calicheamicin derivatives and antibody drug conjugates thereof
US11993625B2 (en) 2017-01-24 2024-05-28 Pfizer, Inc. Calicheamicin derivatives and antibody drug conjugates thereof
US11400086B2 (en) 2017-02-01 2022-08-02 Beyondspring Pharmaceuticals, Inc. Method of reducing chemotherapy-induced neutropenia
WO2018141964A1 (en) 2017-02-06 2018-08-09 Orionis Biosciences Nv Targeted chimeric proteins and uses thereof
WO2018141959A1 (en) 2017-02-06 2018-08-09 Innate Pharma Immunomodulatory antibody drug conjugates binding to a human mica polypeptide
WO2018144999A1 (en) 2017-02-06 2018-08-09 Orionis Biosciences, Inc. Targeted engineered interferon and uses thereof
US11325976B2 (en) 2017-02-16 2022-05-10 Ying Zhang Anti-programmed death-ligand 1 (PD-L1) antibodies and therapeutic uses thereof
WO2018150224A1 (en) 2017-02-16 2018-08-23 Shenzhen Runshin Bioscience Anti-programmed death-ligand 1 (pd-l1) antibodies and therapeutic uses thereof
WO2018152396A1 (en) 2017-02-17 2018-08-23 Innate Tumor Immunity, Inc. Substituted imidazo-quinolines as nlrp3 modulators
EP3753938A1 (en) 2017-02-17 2020-12-23 Innate Tumor Immunity, Inc. Substituted imidazo-quinolines as nlrp3 modulators
CN110337449B (en) * 2017-02-21 2023-08-15 上海君实生物医药科技股份有限公司 anti-PD-L1 antibodies and uses thereof
US11926668B2 (en) 2017-02-21 2024-03-12 Regeneron Pharmaceuticals Inc. Anti-PD-1 antibodies for treatment of lung cancer
US11292842B2 (en) 2017-02-21 2022-04-05 Regeneron Pharmaceuticals, Inc. Anti-PD-1 antibodies for treatment of lung cancer
US11267890B2 (en) 2017-02-21 2022-03-08 Shanghai Junshi Biosciences Inc. Anti-PD-L1 antibody and application thereof
EP3587453A4 (en) * 2017-02-21 2021-07-07 Shanghai Junshi Bioscience Co., Ltd. Anti-pd-l1 antibody and application thereof
CN110337449A (en) * 2017-02-21 2019-10-15 上海君实生物医药科技股份有限公司 Anti- PD-L1 antibody and its application
WO2018154520A1 (en) 2017-02-27 2018-08-30 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2018160841A1 (en) 2017-03-01 2018-09-07 Genentech, Inc. Diagnostic and therapeutic methods for cancer
EP4431109A2 (en) 2017-03-15 2024-09-18 Cue Biopharma, Inc. Combination of multimeric fusion polypeptides and immune checkpoint inhibitor for treating hpv-associated cancer
US11767355B2 (en) 2017-03-15 2023-09-26 Cue Biopharma, Inc. Methods for modulating an immune response
US11958893B2 (en) 2017-03-15 2024-04-16 Cue Biopharma, Inc. Methods for modulating an immune response
US10927161B2 (en) 2017-03-15 2021-02-23 Cue Biopharma, Inc. Methods for modulating an immune response
US11479595B2 (en) 2017-03-15 2022-10-25 Cue Biopharma, Inc. Methods for modulating an immune response
US11993641B2 (en) 2017-03-15 2024-05-28 Cue Biopharma, Inc. Methods for modulating an immune response
WO2018170168A1 (en) 2017-03-15 2018-09-20 Cue Biopharma, Inc. Methods for modulating an immune response
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
US11104712B2 (en) 2017-03-15 2021-08-31 Cue Biopharma, Inc. Methods for modulating an immune response
WO2018167267A1 (en) 2017-03-16 2018-09-20 Innate Pharma Compositions and methods for treating cancer
US11578136B2 (en) 2017-03-16 2023-02-14 Innate Pharma Compositions and methods for treating cancer
WO2018172508A1 (en) 2017-03-24 2018-09-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2018183956A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Naphthyridines as inhibitors of hpk1
WO2018183964A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Isoquinolines as inhibitors of hpk1
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
US11603407B2 (en) 2017-04-06 2023-03-14 Regeneron Pharmaceuticals, Inc. Stable antibody formulation
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018189220A1 (en) 2017-04-13 2018-10-18 F. Hoffmann-La Roche Ag An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer
WO2018191660A1 (en) 2017-04-14 2018-10-18 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2018194496A2 (en) 2017-04-17 2018-10-25 Закрытое Акционерное Общество "Биокад" Monoclonal antibody to pd-l1
EP3613770A4 (en) * 2017-04-17 2021-01-27 Joint Stock Company "Biocad" Monoclonal antibody to pd-l1
US11236167B2 (en) 2017-04-17 2022-02-01 Joint Stock Company “Biocad” Monoclonal antibody to PD-L1
KR102679554B1 (en) 2017-04-17 2024-07-01 조인트 스탁 컴퍼니 “바이오케드” Monoclonal antibodies against PD-L1
KR20190140979A (en) * 2017-04-17 2019-12-20 조인트 스탁 컴퍼니 "바이오케드" Monoclonal antibody against PD-L1
US11326170B2 (en) 2017-04-18 2022-05-10 Changchun Huapu Biotechnology Co. Ltd. Immunomodulatory polynucleotides and uses thereof
WO2018200430A1 (en) 2017-04-26 2018-11-01 Bristol-Myers Squibb Company Methods of antibody production that minimize disulfide bond reduction
US11834448B2 (en) 2017-04-27 2023-12-05 Birdie Biopharmaceuticals, Inc. 2-amino-quinoline derivatives
US11053240B2 (en) 2017-04-27 2021-07-06 Birdie Biopharmaceuticals, Inc. 2-amino-quinoline derivatives
US11654194B2 (en) 2017-05-16 2023-05-23 Jiangsu Hengrui Medicine Co., Ltd. PD-L1 antibody pharmaceutical composition and use thereof
WO2018213297A1 (en) 2017-05-16 2018-11-22 Bristol-Myers Squibb Company Treatment of cancer with anti-gitr agonist antibodies
EP3626266A4 (en) * 2017-05-16 2021-04-07 Jiangsu Hengrui Medicine Co., Ltd. Pd-l1 antibody pharmaceutical composition and use thereof
RU2766590C2 (en) * 2017-05-16 2022-03-15 Цзянсу Хэнжуй Медисин Ко., Лтд. Pharmaceutical composition based on antibody to pd-l1 and its application
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
WO2018219956A1 (en) 2017-05-29 2018-12-06 Gamamabs Pharma Cancer-associated immunosuppression inhibitor
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
EP4306542A2 (en) 2017-05-30 2024-01-17 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
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
US12049503B2 (en) 2017-05-30 2024-07-30 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
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
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
WO2018223040A1 (en) 2017-06-01 2018-12-06 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-pd-1 antibody
US11566073B2 (en) 2017-06-01 2023-01-31 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-PD-1 antibody
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
WO2018220099A1 (en) 2017-06-02 2018-12-06 F. Hoffmann-La Roche Ag Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
US11440960B2 (en) 2017-06-20 2022-09-13 Kymab Limited TIGIT antibodies, encoding nucleic acids and methods of using said antibodies in vivo
US11517567B2 (en) 2017-06-23 2022-12-06 Birdie Biopharmaceuticals, Inc. Pharmaceutical compositions
US11560425B2 (en) 2017-06-27 2023-01-24 Neuracle Science Co., Ltd. Use of anti-FAM19A5 antibodies for treating cancers
WO2019011855A1 (en) 2017-07-10 2019-01-17 Innate Pharma Siglec-9-neutralizing antibodies
WO2019014402A1 (en) 2017-07-14 2019-01-17 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2019018757A1 (en) 2017-07-21 2019-01-24 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2019032431A1 (en) 2017-08-07 2019-02-14 Amgen Inc. Treatment of triple negative breast cancer or colorectal cancer with liver metastases with an anti pd-l1 antibody and an oncolytic virus
WO2019059411A1 (en) 2017-09-20 2019-03-28 Chugai Seiyaku Kabushiki Kaisha Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent
US11939306B2 (en) 2017-09-29 2024-03-26 Curis, Inc. Crystal forms of immunomodulators
US11040948B2 (en) 2017-09-29 2021-06-22 Curis, Inc. Crystal forms of immunomodulators
US11643401B2 (en) 2017-09-29 2023-05-09 Curis, Inc. Crystal forms of immunomodulators
US11840567B2 (en) 2017-10-03 2023-12-12 Joint Stock Company “Biocad” Bispecific antibodies with specific binding to CD47 and PD-L1
WO2019069269A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting) useful in treating hiv
WO2019069270A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting)
WO2019068907A1 (en) 2017-10-06 2019-04-11 Innate Pharma Restoration of t cell activity via the cd39/cd73 axis
WO2019072871A2 (en) 2017-10-09 2019-04-18 Enterome S.A. Microbiota sequence variants of tumor-related antigenic epitopes
WO2019072868A1 (en) 2017-10-10 2019-04-18 Numab Therapeutics AG Multispecific antibody
WO2019072870A1 (en) 2017-10-10 2019-04-18 Numab Innovation Ag Antibodies targeting cd137 and methods of use thereof
US12077588B2 (en) 2017-10-10 2024-09-03 Numab Therapeutics AG Antibodies targeting PDL1 and methods of use thereof
EP3470426A1 (en) 2017-10-10 2019-04-17 Numab Therapeutics AG Multispecific antibody
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
US11680051B2 (en) 2017-10-11 2023-06-20 Aurigene Discovery Technologies Limited Crystalline forms of 3-substituted 1,2,4-oxadiazole
US11136300B2 (en) 2017-10-11 2021-10-05 Aurigene Discovery Technologies Limited Crystalline forms of 3-substituted 1,2,4-oxadiazole
US11525002B2 (en) 2017-10-11 2022-12-13 Board Of Regents, The University Of Texas System Human PD-L1 antibodies and methods of use therefor
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company Methods of treating tumor
US11919957B2 (en) 2017-10-15 2024-03-05 Bristol-Myers Squibb Company Methods of treating tumor
US11613566B2 (en) 2017-10-18 2023-03-28 Alpine Immune Sciences, Inc. Variant ICOS ligand immunomodulatory proteins and related compositions and methods
WO2019079520A2 (en) 2017-10-18 2019-04-25 Alpine Immune Sciences, Inc. Variant icos ligand immunomodulatory proteins and related compositions and methods
WO2019089921A1 (en) 2017-11-01 2019-05-09 Bristol-Myers Squibb Company Immunostimulatory agonistic antibodies for use in treating cancer
US11497734B2 (en) 2017-11-03 2022-11-15 Aurigene Discovery Technologies Limited Dual inhibitors of TIM-3 and PD-1 pathways
US11497735B2 (en) 2017-11-06 2022-11-15 Aurigene Discovery Technologies Limited Conjoint therapies for immunomodulation
WO2019090330A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Methods of treating a tumor
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
US12064418B2 (en) 2017-11-06 2024-08-20 Curis, Inc. Conjoint therapies for immunomodulation
WO2019097369A1 (en) 2017-11-14 2019-05-23 Pfizer Inc. Ezh2 inhibitor combination therapies
WO2019122884A1 (en) 2017-12-19 2019-06-27 Kymab Limited Antibodies to icos
US11629189B2 (en) 2017-12-19 2023-04-18 Kymab Limited Bispecific antibody for ICOS and PD-L1
US11952427B2 (en) 2017-12-27 2024-04-09 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
US11306149B2 (en) 2017-12-27 2022-04-19 Bristol-Myers Squibb Company Anti-CD40 antibodies and uses thereof
US11732044B2 (en) 2017-12-27 2023-08-22 Innovent Biologics (Suzhou) Co., Ltd. Anti-LAG-3 antibody and use thereof
WO2019134946A1 (en) 2018-01-04 2019-07-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma resistant
US11702461B2 (en) 2018-01-09 2023-07-18 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides comprising reduced-affinity immunomodulatory polypeptides
WO2019140150A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2019143607A1 (en) 2018-01-16 2019-07-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2019144126A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
WO2019144098A1 (en) 2018-01-22 2019-07-25 Bristol-Myers Squibb Company Compositions and methods of treating cancer
US11786523B2 (en) 2018-01-24 2023-10-17 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing thrombocytopenia
US11896643B2 (en) 2018-02-05 2024-02-13 Orionis Biosciences, Inc. Fibroblast binding agents and use thereof
WO2019157124A1 (en) 2018-02-08 2019-08-15 Bristol-Myers Squibb Company Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors
WO2019162325A1 (en) 2018-02-21 2019-08-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors
US12090142B2 (en) 2018-02-22 2024-09-17 Board Of Regents, The University Of Texas System Combination therapy for the treatment of cancer
WO2019165434A1 (en) 2018-02-26 2019-08-29 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2019175113A1 (en) 2018-03-12 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers
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
EP3768723A4 (en) * 2018-03-23 2021-12-29 Board of Regents, The University of Texas System Dual specificity antibodies to human pd-l1 and pd-l2 and methods of use therefor
CN112105644B (en) * 2018-03-23 2023-12-05 得克萨斯州大学系统董事会 Dual specific antibodies against human PD-L1 and PD-L2 and methods of use thereof
US11976128B2 (en) 2018-03-23 2024-05-07 Board Of Regents, The University Of Texas System Human PD-L2 antibodies and methods of use therefor
CN112105644A (en) * 2018-03-23 2020-12-18 得克萨斯州大学系统董事会 Dual specific antibodies to human PD-L1 and PD-L2 and methods of use thereof
WO2019190327A2 (en) 2018-03-30 2019-10-03 Merus N.V. Multivalent antibody
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
US11952424B2 (en) 2018-03-30 2024-04-09 Merus N.V. Multivalent antibody
WO2019200256A1 (en) 2018-04-12 2019-10-17 Bristol-Myers Squibb Company Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody
WO2019209896A1 (en) 2018-04-25 2019-10-31 Innate Tumor Immunity, Inc. Nlrp3 modulators
EP4353235A2 (en) 2018-04-25 2024-04-17 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2021089765A1 (en) 2018-05-04 2021-05-14 Tollys Tlr3 ligands that activate both epithelial and myeloid cells
WO2019211492A1 (en) 2018-05-04 2019-11-07 Tollys Tlr3 ligands that activate both epithelial and myeloid cells
WO2019211489A1 (en) 2018-05-04 2019-11-07 Merck Patent Gmbh COMBINED INHIBITION OF PD-1/PD-L1, TGFβ AND DNA-PK FOR THE TREATMENT OF CANCER
WO2019219820A1 (en) 2018-05-16 2019-11-21 Ctxt Pty Limited Substituted condensed thiophenes as modulators of sting
US11613525B2 (en) 2018-05-16 2023-03-28 Ctxt Pty Limited Substituted condensed thiophenes as modulators of sting
WO2019229699A1 (en) 2018-05-31 2019-12-05 Novartis Ag Hepatitis b antibodies
US11932681B2 (en) 2018-05-31 2024-03-19 Novartis Ag Hepatitis B antibodies
WO2019241730A2 (en) 2018-06-15 2019-12-19 Flagship Pioneering Innovations V, Inc. Increasing immune activity through modulation of postcellular signaling factors
WO2019243252A1 (en) 2018-06-18 2019-12-26 Innate Pharma Compositions and methods for treating cancer
US11377503B2 (en) 2018-06-18 2022-07-05 Innate Pharma Antibodies that bind human CD39 and inhibit ATPase activity of a soluble extracellular domain human CD39 polypeptide
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
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
WO2020011964A1 (en) 2018-07-12 2020-01-16 F-Star Beta Limited Antibody molecules that bind pd-l1 and cd137
WO2020014583A1 (en) 2018-07-13 2020-01-16 Bristol-Myers Squibb Company Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a mehtod of treating a cancer or a solid tumor
EP3802577A4 (en) * 2018-07-14 2022-05-18 Development Center for Biotechnology Anti-human pd-l1 antibodies and their uses
CN112805297A (en) * 2018-07-14 2021-05-14 财团法人生物技术开发中心 Anti-human PD-L1 antibodies and uses thereof
CN112805297B (en) * 2018-07-14 2024-08-30 财团法人生物技术开发中心 Anti-human PD-L1 antibodies and uses thereof
WO2020018789A1 (en) 2018-07-18 2020-01-23 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
US11214619B2 (en) 2018-07-20 2022-01-04 Surface Oncology, Inc. Anti-CD112R compositions and methods
US11279758B2 (en) 2018-07-20 2022-03-22 Surface Oncology, Inc. Anti-CD112R compositions and methods
WO2020023551A1 (en) 2018-07-24 2020-01-30 Genentech, Inc. Naphthyridine compounds and uses thereof
WO2020023560A1 (en) 2018-07-24 2020-01-30 F. Hoffmann-La Roche Ag Isoquinoline compounds and uses thereof
WO2020023707A1 (en) 2018-07-26 2020-01-30 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020037094A1 (en) 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Substitued 4-amino-1h-imidazo[4,5-c]quinoline compounds and improved methods for their preparation
WO2020037091A1 (en) 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Imidazo[4,5-c]quinoline derived nlrp3-modulators
WO2020037092A1 (en) 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Imidazo[4,5-c]quinoline derived nlrp3-modulators
EP3841126A4 (en) * 2018-08-20 2022-08-10 1Globe Biomedical Co., Ltd. Novel cancer immunotherapy antibody compositions
WO2020043683A1 (en) 2018-08-27 2020-03-05 Pieris Pharmaceuticals Gmbh Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof
WO2020044206A1 (en) 2018-08-29 2020-03-05 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors for use in the treatment cancer
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020048942A1 (en) 2018-09-04 2020-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses
WO2020053742A2 (en) 2018-09-10 2020-03-19 Novartis Ag Anti-hla-hbv peptide antibodies
WO2020061060A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2020058372A1 (en) 2018-09-19 2020-03-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy
WO2020061377A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
WO2020061349A1 (en) 2018-09-21 2020-03-26 Genentech, Inc. Diagnostic methods for triple-negative breast cancer
EP4249917A2 (en) 2018-09-21 2023-09-27 F. Hoffmann-La Roche AG Diagnostic methods for triple-negative breast cancer
WO2020069402A1 (en) 2018-09-30 2020-04-02 Genentech, Inc. Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
WO2020070053A1 (en) 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of stress granule formation for targeting the regulation of immune responses
WO2020072627A1 (en) 2018-10-02 2020-04-09 Genentech, Inc. Isoquinoline compounds for the treatment of cancer
WO2020072695A1 (en) 2018-10-03 2020-04-09 Genentech, Inc. 8-aminoisoquinoline compounds and uses thereof
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
US11130802B2 (en) 2018-10-10 2021-09-28 Tilos Therapeutics, Inc. Anti-lap antibody variants
WO2020081767A1 (en) 2018-10-18 2020-04-23 Genentech, Inc. Diagnostic and therapeutic methods for sarcomatoid kidney cancer
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
WO2020086724A1 (en) 2018-10-23 2020-04-30 Bristol-Myers Squibb Company Methods of treating tumor
US11564995B2 (en) 2018-10-29 2023-01-31 Wisconsin Alumni Research Foundation Peptide-nanoparticle conjugates
WO2020092304A1 (en) 2018-10-29 2020-05-07 Wisconsin Alumni Research Foundation Dendritic polymers complexed with immune checkpoint inhibitors for enhanced cancer immunotherapy
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
WO2020102728A1 (en) 2018-11-16 2020-05-22 Neoimmunetech, Inc. Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor
WO2020102804A2 (en) 2018-11-16 2020-05-22 Arqule, Inc. Pharmaceutical combination for treatment of cancer
WO2020104496A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Bispecific antibody targeting transferrin receptor 1 and soluble antigen
WO2020104479A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies
WO2020109355A1 (en) 2018-11-28 2020-06-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and kit for assaying lytic potential of immune effector cells
WO2020112781A1 (en) 2018-11-28 2020-06-04 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2020109570A1 (en) 2018-11-30 2020-06-04 Gbg Forschungs Gmbh Method for predicting the response to cancer immunotherapy in cancer patients
WO2020117849A1 (en) 2018-12-04 2020-06-11 Bristol-Myers Squibb Company Methods of analysis using in-sample calibration curve by multiple isotopologue reaction monitoring
EP4198057A1 (en) 2018-12-05 2023-06-21 F. Hoffmann-La Roche AG Diagnostic methods and compositions for cancer immunotherapy
WO2020117952A2 (en) 2018-12-05 2020-06-11 Genentech, Inc. Diagnostic methods and compositions for cancer immunotherapy
WO2020115262A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of cd26 and cd39 as new phenotypic markers for assessing maturation of foxp3+ t cells and uses thereof for diagnostic purposes
WO2020115261A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2020120592A1 (en) 2018-12-12 2020-06-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating melanoma
WO2020127059A1 (en) 2018-12-17 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sulconazole as a furin inhibitor
WO2020132297A1 (en) 2018-12-19 2020-06-25 Cue Biopharma, Inc. Multimeric t-cell modulatory polypeptides and methods of use thereof
WO2020127411A1 (en) 2018-12-19 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d
WO2020127885A1 (en) 2018-12-21 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions for treating cancers and resistant cancers
WO2020132560A2 (en) 2018-12-21 2020-06-25 Aim Immunotech Inc. Compositions and methods for cancer therapy
WO2020136145A2 (en) 2018-12-26 2020-07-02 Innate Pharma Leucocyte immunoglobulin-like receptor neutralizing antibodies
WO2020136147A1 (en) 2018-12-26 2020-07-02 Innate Pharma Compounds and methods for treatment of head and neck cancer
EP3902563A4 (en) * 2018-12-27 2022-12-28 Gigagen, Inc. Anti-pd-l1 binding proteins and methods of use thereof
WO2020136235A1 (en) 2018-12-28 2020-07-02 Transgene Sa M2-defective poxvirus
KR20210110838A (en) 2018-12-28 2021-09-09 트랜스진 에스.에이. M2 defective poxvirus
WO2020150114A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Heterocyclic nlrp3 modulators, for use in the treatment of cancer
WO2020150113A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Substituted quinazolines as nlrp3 modulators, for use in the treatment of cancer
WO2020150152A1 (en) 2019-01-14 2020-07-23 Genentech, Inc. Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine
WO2020150116A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2020150115A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2020148338A1 (en) 2019-01-15 2020-07-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy
WO2020157131A1 (en) 2019-01-30 2020-08-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor
WO2020161083A1 (en) 2019-02-04 2020-08-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating blood-brain barrier
WO2020163589A1 (en) 2019-02-08 2020-08-13 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2020165370A1 (en) 2019-02-13 2020-08-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for selecting a cancer treatment in a subject suffering from cancer
WO2020169472A2 (en) 2019-02-18 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of inducing phenotypic changes in macrophages
EP3929213A4 (en) * 2019-02-21 2023-03-08 Eucure (Beijing) Biopharma Co., Ltd Anti-pd-l1 antibody and use thereof
WO2020186176A1 (en) 2019-03-14 2020-09-17 Genentech, Inc. Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab
WO2020198672A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020198676A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020205626A1 (en) 2019-03-29 2020-10-08 Genentech, Inc. Modulators of cell surface protein interactions and methods and compositions related to same
WO2020201362A2 (en) 2019-04-02 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
WO2020201568A1 (en) 2019-04-03 2020-10-08 Targimmune Therapeutics Ag Immunotherapy for the treatment of cancer
WO2020208060A1 (en) 2019-04-09 2020-10-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk2 inhibitors in combination with immune checkpoint blockade therapy for the treatment of cancer
WO2020212484A1 (en) 2019-04-17 2020-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treatment of nlrp3 inflammasome mediated il-1beta dependent disorders
WO2020214995A1 (en) 2019-04-19 2020-10-22 Genentech, Inc. Anti-mertk antibodies and their methods of use
WO2020216697A1 (en) 2019-04-23 2020-10-29 Innate Pharma Cd73 blocking antibodies
WO2020221796A1 (en) 2019-04-30 2020-11-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
WO2020226986A2 (en) 2019-05-03 2020-11-12 Genentech, Inc. Methods of treating cancer with an anti-pd-l1 antibody
WO2020227159A2 (en) 2019-05-03 2020-11-12 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity
WO2020232378A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use
WO2020232375A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Oxoacridinyl acetic acid derivatives and methods of use
WO2020234875A2 (en) 2019-05-19 2020-11-26 Yeda Research And Development Co. Ltd. Identification of recurrent mutated neopeptides
WO2020239558A1 (en) 2019-05-24 2020-12-03 Pfizer Inc. Combination therapies using cdk inhibitors
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
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
EP3929215A4 (en) * 2019-06-10 2022-06-22 Shandong Boan Biotechnology Co., Ltd. Bifunctional fusion protein against pdl1 and tgf? and use thereof
WO2021009267A1 (en) 2019-07-15 2021-01-21 Capella Bioscience Ltd Anti-pd-l1 antibodies
WO2021009365A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting
WO2021009362A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting
WO2021019526A1 (en) 2019-07-29 2021-02-04 Yeda Research And Development Co. Ltd. Methods of treating and diagnosing lung cancer
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
WO2021048292A1 (en) 2019-09-11 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
WO2021055994A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
WO2021062018A1 (en) 2019-09-25 2021-04-01 Bristol-Myers Squibb Company Composite biomarker for cancer therapy
EP4424321A2 (en) 2019-09-27 2024-09-04 F. Hoffmann-La Roche AG Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021062085A1 (en) 2019-09-27 2021-04-01 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021064567A1 (en) 2019-09-30 2021-04-08 Astrazeneca Ab Combination treatment for cancer
EP3800201A1 (en) 2019-10-01 2021-04-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Cd28h stimulation enhances nk cell killing activities
WO2021064180A1 (en) 2019-10-03 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating macrophages polarization
WO2021064184A1 (en) 2019-10-04 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer
WO2021074391A1 (en) 2019-10-17 2021-04-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing nasal intestinal type adenocarcinomas
KR20220088425A (en) 2019-10-25 2022-06-27 다이이찌 산쿄 가부시키가이샤 Combination of anti-GARP antibodies and immunomodulators
WO2021079958A1 (en) 2019-10-25 2021-04-29 第一三共株式会社 Combination of anti-garp antibody and immunoregulator
WO2021083959A1 (en) 2019-10-29 2021-05-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating uveal melanoma
WO2021090146A1 (en) 2019-11-04 2021-05-14 Astrazeneca Ab Combination therapy for treating cancer
WO2021091964A1 (en) 2019-11-04 2021-05-14 Duke University Treatment for primary and metastatic 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
WO2021092171A1 (en) 2019-11-06 2021-05-14 Genentech, Inc. Diagnostic and therapeutic methods for treatment of hematologic cancers
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
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
WO2021106978A1 (en) 2019-11-27 2021-06-03 サイトリミック株式会社 Pharmaceutical composition
WO2021127217A1 (en) 2019-12-17 2021-06-24 Flagship Pioneering Innovations V, Inc. Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly
WO2021123243A1 (en) 2019-12-19 2021-06-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and vaccine compositions to treat cancers
WO2021127554A1 (en) 2019-12-19 2021-06-24 Bristol-Myers Squibb Company Combinations of dgk inhibitors and checkpoint antagonists
WO2021142203A1 (en) 2020-01-10 2021-07-15 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2021144426A1 (en) 2020-01-17 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2021154073A1 (en) 2020-01-29 2021-08-05 Merus N.V. Means and method for modulating immune cell engaging effects.
WO2021152548A1 (en) 2020-01-30 2021-08-05 Benitah Salvador Aznar Combination therapy for treatment of cancer and cancer metastasis
WO2021155149A1 (en) 2020-01-31 2021-08-05 Genentech, Inc. Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine
WO2021156360A1 (en) 2020-02-05 2021-08-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki)
WO2021158938A1 (en) 2020-02-06 2021-08-12 Bristol-Myers Squibb Company Il-10 and uses thereof
WO2021158635A1 (en) 2020-02-07 2021-08-12 Al Therapeutics, Inc. Anti-viral compositions and methods of use
WO2021174045A1 (en) 2020-02-28 2021-09-02 Bristol-Myers Squibb Company Radiolabeled fibronectin based scaffolds and antibodies and theranostic uses thereof
WO2021170777A1 (en) 2020-02-28 2021-09-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing, prognosing and managing treatment of breast cancer
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
WO2021178807A1 (en) 2020-03-06 2021-09-10 Celgene Quanticel Research, Inc. Combination of an lsd-1 inhibitor and nivolumab for use in treating sclc or sqnsclc
WO2021176424A1 (en) 2020-03-06 2021-09-10 Ona Therapeutics, S.L. Anti-cd36 antibodies and their use to treat cancer
EP3878446A1 (en) 2020-03-09 2021-09-15 Universite De Geneve Hsd11b1 inhibitors for use in immunotherapy and uses thereof
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
WO2021180643A1 (en) 2020-03-09 2021-09-16 Universite De Geneve Hsd11b1 inhibitors for use in immunotherapy and uses thereof
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021195485A1 (en) * 2020-03-27 2021-09-30 Vanderbilt University Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (sars-cov-2)
WO2021202959A1 (en) 2020-04-03 2021-10-07 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2021205444A1 (en) 2020-04-06 2021-10-14 Yeda Research And Development Co. Ltd. Methods of diagnosing cancer and predicting responsiveness to therapy
WO2021207449A1 (en) 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
US12018065B2 (en) 2020-04-27 2024-06-25 Twist Bioscience Corporation Variant nucleic acid libraries for coronavirus
WO2021222167A1 (en) 2020-04-28 2021-11-04 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
WO2021224215A1 (en) 2020-05-05 2021-11-11 F. Hoffmann-La Roche Ag Predicting response to pd-1 axis inhibitors
US11878062B2 (en) 2020-05-12 2024-01-23 Cue Biopharma, Inc. Multimeric T-cell modulatory polypeptides and methods of use thereof
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
WO2021239838A2 (en) 2020-05-26 2021-12-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes
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
WO2021249969A1 (en) 2020-06-10 2021-12-16 Merck Patent Gmbh Combination product for the treatment of cancer diseases
WO2021252977A1 (en) 2020-06-12 2021-12-16 Genentech, Inc. Methods and compositions for cancer immunotherapy
WO2021257503A1 (en) 2020-06-16 2021-12-23 Genentech, Inc. Methods and compositions for treating triple-negative breast cancer
WO2021257124A1 (en) 2020-06-18 2021-12-23 Genentech, Inc. Treatment with anti-tigit antibodies and pd-1 axis binding antagonists
WO2022006179A1 (en) 2020-06-29 2022-01-06 Flagship Pioneering Innovations V, Inc. Viruses engineered to promote thanotransmission and their use in treating cancer
WO2022008519A1 (en) 2020-07-07 2022-01-13 BioNTech SE Therapeutic rna for hpv-positive cancer
WO2022020716A1 (en) 2020-07-24 2022-01-27 Genentech, Inc. Heterocyclic inhibitors of tead for treating cancer
WO2022023379A1 (en) 2020-07-28 2022-02-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for preventing and treating a cancer
WO2022036146A1 (en) 2020-08-12 2022-02-17 Genentech, Inc. Diagnostic and therapeutic methods for cancer
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
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022050954A1 (en) 2020-09-04 2022-03-10 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
US12029782B2 (en) 2020-09-09 2024-07-09 Cue Biopharma, Inc. MHC class II T-cell modulatory multimeric polypeptides for treating type 1 diabetes mellitus (T1D) and methods of use thereof
WO2022053703A1 (en) 2020-09-14 2022-03-17 Boehringer Ingelheim International Gmbh Heterologous prime boost vaccine
US12121565B2 (en) 2020-09-14 2024-10-22 Duke University Methods of treatment of specific cancers with NLRP3 inhibitors and anti-PD1/PD-L1 antibodies
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
WO2022076596A1 (en) 2020-10-06 2022-04-14 Codiak Biosciences, Inc. Extracellular vesicle-aso constructs targeting stat6
WO2022074152A1 (en) 2020-10-08 2022-04-14 Targimmune Therapeutics Ag Immunotherapy for the treatment of cancer
WO2022084210A1 (en) 2020-10-20 2022-04-28 F. Hoffmann-La Roche Ag Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors
WO2022084531A1 (en) 2020-10-23 2022-04-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating glioma
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022094567A1 (en) 2020-10-28 2022-05-05 Ikena Oncology, Inc. Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
WO2022101302A1 (en) 2020-11-12 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes
WO2022103904A1 (en) 2020-11-13 2022-05-19 Genentech, Inc. Methods and compositions comprising a krasg12c inhibitor and a pd-l1 binding antagonist for treating lung cancer
WO2022101481A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
WO2022101484A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
WO2022101463A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death
WO2022119830A1 (en) 2020-12-02 2022-06-09 Genentech, Inc. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022136257A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022136255A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022135667A1 (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
WO2022135666A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022148736A1 (en) 2021-01-05 2022-07-14 Transgene Vectorization of muc1 t cell engager
WO2022183018A1 (en) * 2021-02-26 2022-09-01 Fred Hutchinson Cancer Research Center Protective antibodies against respiratory viral infections
WO2022194908A1 (en) 2021-03-17 2022-09-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2022203090A1 (en) 2021-03-25 2022-09-29 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 for treatment of cancer
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
WO2022212784A1 (en) 2021-03-31 2022-10-06 Flagship Pioneering Innovations V, Inc. Thanotransmission polypeptides and their use in treating cancer
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022217123A2 (en) 2021-04-08 2022-10-13 Nurix Therapeutics, Inc. Combination therapies with cbl-b inhibitor compounds
WO2022216898A1 (en) 2021-04-09 2022-10-13 Genentech, Inc. Combination therapy with a raf inhibitor and a pd-1 axis inhibitor
WO2022219080A1 (en) 2021-04-14 2022-10-20 INSERM (Institut National de la Santé et de la Recherche Médicale) New method to improve nk cells cytotoxicity
WO2022223791A1 (en) 2021-04-23 2022-10-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cell senescence accumulation related disease
WO2022229966A1 (en) 2021-04-29 2022-11-03 Yeda Research And Development Co. Ltd. T cell receptors directed against ras-derived recurrent neoantigens and methods of identifying same
WO2022232503A1 (en) 2021-04-30 2022-11-03 Genentech, Inc. Therapeutic and diagnostic methods and compositions for cancer
WO2022243378A1 (en) 2021-05-18 2022-11-24 Kymab Limited Uses of anti-icos antibodies
WO2022254227A1 (en) 2021-06-04 2022-12-08 Kymab Limited Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies
WO2023278641A1 (en) 2021-06-29 2023-01-05 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
WO2023279092A2 (en) 2021-07-02 2023-01-05 Genentech, Inc. Methods and compositions for treating cancer
WO2023280790A1 (en) 2021-07-05 2023-01-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Gene signatures for predicting survival time in patients suffering from renal cell carcinoma
WO2023285552A1 (en) 2021-07-13 2023-01-19 BioNTech SE Multispecific binding agents against cd40 and cd137 in combination therapy for cancer
WO2023010095A1 (en) 2021-07-28 2023-02-02 F. Hoffmann-La Roche Ag Methods and compositions for treating cancer
WO2023010094A2 (en) 2021-07-28 2023-02-02 Genentech, Inc. Methods and compositions for treating cancer
WO2023007472A1 (en) 2021-07-30 2023-02-02 ONA Therapeutics S.L. Anti-cd36 antibodies and their use to treat cancer
WO2023051926A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
WO2023056403A1 (en) 2021-09-30 2023-04-06 Genentech, Inc. Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists
WO2023052531A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
WO2023057882A1 (en) 2021-10-05 2023-04-13 Pfizer Inc. Combinations of azalactam compounds with a pd-1 axis binding antagonist for the treatment of cancer
WO2023061930A1 (en) 2021-10-11 2023-04-20 BioNTech SE Therapeutic rna for lung cancer
WO2023077034A1 (en) 2021-10-28 2023-05-04 Lyell Immunopharma, Inc. Methods for culturing immune cells
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
WO2023079428A1 (en) 2021-11-03 2023-05-11 Pfizer Inc. Combination therapies using tlr7/8 agonist
WO2023078900A1 (en) 2021-11-03 2023-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating triple negative breast cancer (tnbc)
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
WO2023083868A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
WO2023083439A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
WO2023088968A1 (en) 2021-11-17 2023-05-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Universal sarbecovirus vaccines
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
US12110276B2 (en) 2021-11-24 2024-10-08 Genentech, Inc. Pyrazolo compounds and methods of use thereof
WO2023118165A1 (en) 2021-12-21 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2023129438A1 (en) 2021-12-28 2023-07-06 Wisconsin Alumni Research Foundation Hydrogel compositions for use for depletion of tumor associated macrophages
WO2023137161A1 (en) 2022-01-14 2023-07-20 Amgen Inc. Triple blockade of tigit, cd112r, and pd-l1
WO2023147371A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
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
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023192478A1 (en) 2022-04-01 2023-10-05 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2023196987A1 (en) 2022-04-07 2023-10-12 Bristol-Myers Squibb Company Methods of treating tumor
WO2023196964A1 (en) 2022-04-08 2023-10-12 Bristol-Myers Squibb Company Machine learning identification, classification, and quantification of tertiary lymphoid structures
WO2023201299A1 (en) 2022-04-13 2023-10-19 Genentech, Inc. Pharmaceutical compositions of therapeutic proteins and methods of use
WO2023201291A1 (en) 2022-04-13 2023-10-19 Genentech, Inc. Pharmaceutical compositions of mosunetuzumab and methods of use
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023220703A1 (en) 2022-05-12 2023-11-16 Genentech, Inc. Methods and compositions comprising a shp2 inhibitor and a pd-l1 binding antagonist
WO2023222854A1 (en) 2022-05-18 2023-11-23 Kymab Limited Uses of anti-icos antibodies
WO2023228095A1 (en) 2022-05-24 2023-11-30 Daiichi Sankyo Company, Limited Dosage regimen of an anti-cdh6 antibody-drug conjugate
WO2023235415A1 (en) 2022-06-01 2023-12-07 Genentech, Inc. Method to identify a patient with an increased likelihood of chemotherapy-induced peripheral neuropathy
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
WO2024015897A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024023740A1 (en) 2022-07-27 2024-02-01 Astrazeneca Ab Combinations of recombinant virus expressing interleukin-12 with pd-1/pd-l1 inhibitors
WO2024023750A1 (en) 2022-07-28 2024-02-01 Astrazeneca Uk Limited Combination of antibody-drug conjugate and bispecific checkpoint inhibitor
WO2024033399A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sigmar1 ligand for the treatment of pancreatic cancer
WO2024033400A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sk2 inhibitor for the treatment of pancreatic cancer
WO2024049949A1 (en) 2022-09-01 2024-03-07 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2024052356A1 (en) 2022-09-06 2024-03-14 Institut National de la Santé et de la Recherche Médicale Inhibitors of the ceramide metabolic pathway for overcoming immunotherapy resistance in cancer
WO2024054992A1 (en) 2022-09-09 2024-03-14 Bristol-Myers Squibb Company Methods of separating chelator
WO2024056716A1 (en) 2022-09-14 2024-03-21 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy
WO2024069009A1 (en) 2022-09-30 2024-04-04 Alentis Therapeutics Ag Treatment of drug-resistant hepatocellular carcinoma
WO2024077191A1 (en) 2022-10-05 2024-04-11 Flagship Pioneering Innovations V, Inc. Nucleic acid molecules encoding trif and additionalpolypeptides and their use in treating cancer
WO2024077095A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
WO2024077166A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
WO2024084034A1 (en) 2022-10-21 2024-04-25 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of osteoarthritis
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
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
WO2024094688A1 (en) 2022-11-01 2024-05-10 Heidelberg Pharma Research Gmbh Anti-gucy2c antibody and uses thereof
WO2024116140A1 (en) 2022-12-01 2024-06-06 Medimmune Limited Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies
WO2024115725A1 (en) 2022-12-01 2024-06-06 BioNTech SE Multispecific antibody against cd40 and cd137 in combination therapy with anti-pd1 ab and chemotherapy
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
WO2024137589A2 (en) 2022-12-20 2024-06-27 Genentech, Inc. Methods of treating pancreatic cancer with a pd-1 axis binding antagonist and an rna vaccine
WO2024137776A1 (en) 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Combination therapy for lung cancer
WO2024151687A1 (en) 2023-01-09 2024-07-18 Flagship Pioneering Innovations V, Inc. Genetic switches and their use in treating cancer
WO2024150177A1 (en) 2023-01-11 2024-07-18 Advesya Treatment methods for solid tumors
WO2024150017A1 (en) 2023-01-13 2024-07-18 Akrivia Biomedics Limited Method of profiling diseases
WO2024160721A1 (en) 2023-01-30 2024-08-08 Kymab Limited Antibodies
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy
WO2024200571A1 (en) 2023-03-28 2024-10-03 Institut National de la Santé et de la Recherche Médicale Method for discriminating mono-immunotherapy from combined immunotherapy in cancers

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