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WO2025054110A1 - Polythérapie à base d'un antagoniste de pd-1 et d'un antagoniste de lag3 pour le traitement de patients atteints d'un cancer avant et/ou après chirurgie - Google Patents

Polythérapie à base d'un antagoniste de pd-1 et d'un antagoniste de lag3 pour le traitement de patients atteints d'un cancer avant et/ou après chirurgie Download PDF

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Publication number
WO2025054110A1
WO2025054110A1 PCT/US2024/044966 US2024044966W WO2025054110A1 WO 2025054110 A1 WO2025054110 A1 WO 2025054110A1 US 2024044966 W US2024044966 W US 2024044966W WO 2025054110 A1 WO2025054110 A1 WO 2025054110A1
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Prior art keywords
antagonist
antibody
lag3
cancer
surgical resection
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Inventor
Roman GROISBERG
Burak GUMUSCU
Fan Jin
Jianda YUAN
Nageatte IBRAHIM
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to combination therapies useful for the treatment of cancer before and/or after surgery.
  • the invention relates to a combination therapy that comprises an antagonist of a Programmed Death 1 protein (PD-1), and an antagonist of Lymphocyte- Activation Gene 3 (LAG3).
  • PD-1 Programmed Death 1 protein
  • LAG3 Lymphocyte- Activation Gene 3
  • PD-1 is recognized as an important molecule in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and Natural Killer T (NKT) cells and up-regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells (1).
  • NKT Natural Killer T
  • PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma (14-15) and to correlate with poor prognosis in renal cancer (16).
  • PD-L1 expressing tumor cells interact with PD-1 expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.
  • Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of indications.
  • IgG4 immunoglobulin G4
  • Lymphocyte-Activation Gene 3 is an inhibitory immune modulatory receptor that regulates effector T cell homeostasis, proliferation, and activation, and has a role in the suppressor activity of regulatory T cells (Tregs).
  • LAG3 is expressed on activated CD8+ and CD4+ T cells, Tregs and the Tri regulatory T-cell population, as well as on natural killer cells and a subset of tolerogenic plasmacytoid dendritic cells. Because of its proposed role on both effector T cells and Tregs, LAG3 is one of several immune checkpoint molecules where simultaneous blockade of both cell populations has the potential to enhance antitumor immunity.
  • LAG3 is structurally related to cluster of differentiation (CD) 4 and a member of the immunoglobulin (Ig) superfamily. Like CD4, its ligand is major histocompatibility complex (MHC) Class II molecules. Interaction with its ligand leads to dimerization and signal transduction resulting in altered T-cell activation. Following T-cell activation, LAG3 is transiently expressed on the cell surface. A large proportion of LAG3 molecules are found in intracellular stores and can be rapidly translocated to the cell membrane upon T-cell activation. LAG3 expression is regulated at the cell surface by extracellular cleavage to yield a soluble form of LAG3 (sLAG 3), which can be detected in serum. Expression of LAG3 is tightly regulated and represents a self-limiting mechanism to counter uncontrolled T-cell activity.
  • MHC major histocompatibility complex
  • the invention provides a method for treating cancer in an individual comprising administering to the individual a combination therapy that comprises a PD-1 antagonist and a LAG3 antagonist before and/or after resection of a tumor.
  • the combination therapy is administered before and after resection of a tumor.
  • the cancer is cutaneous squamous cell carcinoma, melanoma, esophageal cancer, breast cancer, bladder cancer or lung cancer.
  • the cancer is cutaneous squamous cell carcinoma, esophageal cancer, breast cancer, bladder cancer or lung cancer.
  • the cancer is cutaneous squamous cell carcinoma at Stage II, III or IV.
  • the cancer is cutaneous squamous cell carcinoma at Stage I, II, III or IV.
  • the PD-1 antagonist and LAG3 antagonist are co-formulated.
  • the PD-1 antagonist is an anti -PD-1 antibody that blocks the binding of PD-1 to PD-L1 and PD-L2.
  • the LAG3 antagonist is an anti-LAG3 antibody that blocks the binding of LAG3 to MHC Class II molecules.
  • VH Immunoglobulin heavy chain variable region VK Immunoglobulin kappa light chain variable region
  • Favezelimab is defined in the World Health Organization drug information INN Vol. 35, No. l, 2021. Favezelimab corresponds with the monoclonal antibody that consists of two heavy chain and two light chain sequences of SEQ ID NO: 23 and SEQ ID NO: 22, respectively.
  • host cells e.g., CHO cells
  • post-translational modifications can occur (e.g., C-terminal Lysine clipping in the heavy chain, conversion of the N-terminal glutamine to pyroglutamate or pyroglutamic acid in the heavy chain).
  • a “Favezelimab variant” means a monoclonal antibody that comprises heavy chain and light chain sequences that are substantially identical to those in Favezelimab described herein, except for having three, two or one conservative amino acid substitutions in the light chain sequence at positions that are located outside of the light chain CDRs and/or six, five, four, three, two or one conservative amino acid substitutions in the heavy chain sequence that are located outside of the heavy chain CDRs, e.g., the variant positions are located in the FR regions or the constant region.
  • Favezelimab and a Favezelimab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively.
  • a Favezelimab variant is substantially the same as Favezelimab with respect to the following properties: binding affinity to human LAG3 and ability to block the binding of human LAG3 to human MHC Class II.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • subject includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes 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 the heavy chain may define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • 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).
  • variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, the same.
  • variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • the CDRs are usually aligned by the framework regions, supporting binding to a specific epitope.
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al. National Institutes of Health, Bethesda, Md. ; 5 th ed.; NIH Publ. No.
  • antibody fragment or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions.
  • Human antibody refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody or rat antibody refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.
  • an anti-tumor response to a combination therapy described herein is assessed using RECIST 1.1 criteria, bidimentional irRC or unidimensional irRC.
  • an anti-tumor response is any of SD, PR, CR, PFS, or DFS.
  • Chemotherapeutic agents useful in the treatment methods of the present invention include cytostatic and/or cytotoxic agents.
  • Chothia as used herein means an antibody numbering system described in Al- Lazikani etal., JMB 273:927-948 (1997).
  • Consists essentially of and variations such as “consist essentially of’ or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion of other elements, of similar or different nature than the recited elements, that do not materially change the basic or novel properties of the specified dosage regimen, method, or composition.
  • a PD-1 antagonist that consists essentially of a recited amino acid sequence may also include one or more amino acids, including substitutions of one or more amino acid residues, which do not materially affect the properties of the binding compound.
  • DCR or “Disease Control Rate” means CR + PR + SD.
  • Diagnostic anti-PD-L monoclonal antibody means a mAb that specifically binds to the mature form of the designated PD-L (PD-L1 or PDL2) that is expressed on the surface of certain mammalian cells. A mature PD-L lacks the presecretory leader sequence, also referred to as leader peptide.
  • the terms “PD-L” and “mature PD-L” are used interchangeably herein, and shall be understood to mean the same molecule unless otherwise indicated or readily apparent from the context.
  • a diagnostic anti -human PD-L1 mAb or an anti-hPD-Ll mAb refers to a monoclonal antibody that specifically binds to mature human PD-L1.
  • a mature human PD-L1 molecule consists of amino acids 19-290 of the following sequence: MRI FAVFI FMTYWHLLNAFTVTVPKDLYWEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNI IQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITV KVNAPYNKINQRILWDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFN VTSTLRINTTTNEI FYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALT
  • diagnostic anti-human PD-L1 mAbs useful as diagnostic mAbs for immunohistochemistry (IHC) detection of PD-L 1 expression in formalin-fixed, paraffin- embedded (FFPE) tumor tissue sections are antibody 20C3 and antibody 22C3, which are described in W02014/100079.
  • Another anti-human PD-L1 mAb that has been reported to be useful for IHC detection of PD-L1 expression in FFPE tissue sections Choen, B.J. et al., Clin Cancer Res 19: 3462-3473 (2013)
  • PD -LI or “PD-L2” expression as used herein means any detectable level of expression of the designated PD-L protein on the cell surface or of the designated PD-L mRNA within a cell or tissue.
  • PD-L protein expression may be detected with a diagnostic PD-L antibody in an IHC assay of a tumor tissue section or by flow cytometry.
  • PD-L protein expression by tumor cells may be detected by PET imaging, using a binding agent (e.g., antibody fragment, affibody and the like) that specifically binds to the desired PD-L target, e.g., PD-L1 or PD-L2.
  • a binding agent e.g., antibody fragment, affibody and the like
  • Techniques for detecting and measuring PD-L mRNA expression include RT- PCR, realtime quantitative RT-PCR, RNAseq, and the Nanostring platform (J Clin. Invest.
  • One approach employs a simple binary end-point of positive or negative for PD-L1 expression, with a positive result defined in terms of the percentage of tumor cells that exhibit histologic evidence of cell-surface membrane staining.
  • a tumor tissue section is counted as positive for PD-L1 expression if it is at least 1% of total tumor cells.
  • PD-L1 expression in the tumor tissue section is quantified in the tumor cells as well as in infiltrating immune cells, which predominantly comprise lymphocytes.
  • the percentage of tumor cells and infiltrating immune cells that exhibit membrane staining are separately quantified as ⁇ 5%, 5 to 9%, and then in 10% increments up to 100%.
  • PD-L1 expression in the immune infiltrate is reported as a semi -quantitative measurement called the adjusted inflammation score (AIS), which is determined by multiplying the percent of membrane staining cells by the intensity of the infiltrate, which is graded as none (0), mild (score of 1, rare lymphocytes), moderate (score of 2, focal infiltration of tumor by lymphohistiocytic aggregates), or severe (score of 3, diffuse infiltration).
  • AIS adjusted inflammation score
  • the level of PD-L mRNA expression may be compared to the mRNA expression levels of one or more reference genes that are frequently used in quantitative RT-PCR.
  • a level of PD-L1 expression (protein and/or mRNA) by malignant cells and/or by infiltrating immune cells within a tumor is determined to be “overexpressed” or “elevated” based on comparison with the level of PD-L 1 expression (protein and/ or mRNA) by an appropriate control.
  • a control PD-L1 protein or mRNA expression level may be the level quantified in nonmalignant cells of the same type or in a section from a matched normal tissue.
  • PD-L1 expression in a tumor sample is determined to be elevated if PD-L1 protein (and/or PD-L1 mRNA) in the sample is at least 10%, 20%, or 30% greater than in the control.
  • TPS Tumor Proportion Score
  • MIMS Mononuclear inflammatory density score
  • Combined positive score refers to the ratio of the number of PD-L 1 positive tumor cells and PD-L1 positive mononuclear inflammatory cells (MIC) within the tumor nests and the adjacent supporting stroma (numerator) compared to the total number of tumor cells (denominator; i.e., the number of PD-L1 positive and PD-L1 negative tumor cells).
  • PD-L1 expression at any intensity is considered positive, i.e., weak (1+), moderate (2+), or strong (3+).
  • PD-L1 expression positive refers to a Tumor Proportion Score, Mononuclear Inflammatory Density Score or Combined Positive Score of at least 1%; AIS is > 5; or elevated level of PD-L1 expression (protein and/or mRNA) by malignant cells and/or by infiltrating immune cells within a tumor compared to an appropriate control.
  • DSDR or “Durable Stable Disease Rate” means SD for > 23 weeks.
  • Framework region or “FR” as used herein means the immunoglobulin variable regions excluding the CDR regions.
  • “Kabaf ’ as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).
  • LAG3 antagonist means any chemical compound or biological molecule that blocks binding of LAG3 expressed on an immune cell (T cell, Tregs, or NK cell etc.) to its ligand(s), for example, MHC Class II molecules.
  • Human LAG3 comprises the amino acid sequence: MWEAQFLGLL FLQPLWVAPV KPLQPGAEVP WWAQEGAPA QLPCSPTI PL QDLSLLRRAG VTWQHQPDSG PPAAAPGHPL APGPHPAAPS SWGPRPRRYT VLSVGPGGLR SGRLPLQPRV QLDERGRQRG DFSLWLRPAR RADAGEYRAA VHLRDRALSC RLRLRLGQAS MTASPPGSLR ASDWVILNCS FSRPDRPASV HWFRNRGQGR VPVRESPHHH LAESFLFLPQ VSPMDSGPWG CILTYRDGFN VSIMYNLTVL GLEPPTPLTV YAGAGSRVGL PCRLPAGVGT RSFLTAKWTP
  • MSI Melatonin-associated telomere
  • NCI National Cancer Institute
  • BAT25 GenBank accession no. 9834508
  • BAT26 GeneBank accession no. 9834505
  • D5S346 GeneBank accession no. 181171
  • D2S123 GeneBank accession no. 187953
  • DI 7S250 GeneBank accession no. 177030
  • BAT40, BAT34C4, TGF-P-RII and ACTC can be used.
  • kits for MSI analysis include, for example, the Promega MSI multiplex PCR assay, FoundationOne® CDx (FICDx) next generation sequencing based in vitro diagnostic device using DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens.
  • FICDx FoundationOne® CDx
  • MSI-H microsatellite instability-high
  • Low frequency microsatellite instability or “microsatellite instability -low (MSI-L)” refers to if one of the five NCI markers indicated above show instability or ⁇ 30-40% of the total markers exhibit instability (i.e. have insertion/deletion mutations).
  • Non-MSI-H colorectal cancer refers to microsatellite stable (MSS) and low frequency MSI (MSI-L) colorectal cancer.
  • Microsatellite Stable refers to if none of the five NCI markers indicated above show instability (i.e. have insertion/deletion mutations)
  • pMMR Proficient mismatch repair
  • MMR proteins MMH1, PMS2, MSH2, and MSH6
  • kits for MMR analysis include the Ventana MMR IHC assay.
  • MMR mis repair deficient colorectal cancer
  • MMR protein(s) MMR protein(s)
  • MSH1 MMR protein(s)
  • MSH6 MMR protein(s)
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol.
  • Non-responder patient when referring to a specific anti-tumor response to treatment with a combination therapy described herein, means the patient did not exhibit the anti-tumor response.
  • ORR or “objective response rate” refers in some embodiments to CR + PR
  • ORR(week24) refers to CR and PR measured using irRECIST in each patient in a cohort after 24 weeks of anti-cancer treatment .
  • Patient or “subject” refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients such as cattle, horses, dogs, and cats.
  • PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressing PD-1.
  • Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
  • the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1.
  • Human PD-1 amino acid sequences can be found in NCBI Locus No.:
  • Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
  • Pembrolizumab also known as MK-3475, is a humanized IgG4 mAb with the structure described in WHO Drug Information , Vol. 27, No. 2, pages 161-162 (2013). Pembrolizumab corresponds with the monoclonal antibody that consists of two heavy chain and two light chain sequences of SEQ ID NO: 10 and SEQ ID NO: 5, respectively.
  • host cells e.g., CHO cells
  • post- translational modifications can occur (e.g., C-terminal Lysine clipping in the heavy chain, conversion of the N-terminal glutamine to pyroglutamate or pyroglutamic acid in the heavy chain).
  • a “pembrolizumab variant” means a monoclonal antibody that comprises heavy chain and light chain sequences that are substantially identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions in the light chain at positions that are located outside of the light chain CDRs and/or six, five, four, three, two or one conservative amino acid substitutions in the heavy chain that are located outside of the heavy chain CDRs, e.g, the variant positions are located in the FR regions or the constant region.
  • pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively.
  • a pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1.
  • RECIST 1.1 Response Criteria means the definitions set forth in Eisenhauer et al., E.A. et al., Enr. J Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.
  • Responder patient when referring to a specific anti-tumor response to treatment with a combination therapy described herein, means the patient exhibited the anti-tumor response.
  • sustained response means a sustained therapeutic effect after cessation of treatment with a therapeutic agent, or a combination therapy described herein.
  • the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.
  • Tissue Section refers to a single part or piece of a tissue sample, e.g., a thin slice of tissue cut from a sample of a normal tissue or of a tumor.
  • “Treat” or “treating” cancer as used herein means to administer a combination therapy comprising a PD-1 antagonist and a LAG3 antagonist to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect on the cancer, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth.
  • Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50: 1 S- 10S (2009)).
  • a T/C ⁇ 42% is the minimum level of anti -tumor activity.
  • response to a combination therapy described herein is assessed using RECIST 1 .1 criteria or irRC (bidimensional or unidimensional) and the treatment achieved by a combination of the invention is any of PR, CR, OR, PFS, DFS and OS.
  • PFS also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD.
  • DFS refers to the length of time during and after treatment that the patient remains free of disease.
  • OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients.
  • response to a combination of the invention is any of PR, CR, PFS, DFS, OR and OS that is assessed using RECIST 1.1 response criteria.
  • the treatment regimen for a combination of the invention that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject.
  • any of the aspects of the invention may not be effective in achieving a positive therapeutic effect on the cancer in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi 2 -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon- test.
  • treatment regimen “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination of the invention.
  • Treatment cycle refers to a repeating dosing interval between completion of the first doses of the PD-1 antagonist and LAG3 antagonist and completion of the second doses of the PD-1 antagonist and LAG3 antagonist.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).
  • Tumor burden also referred to as “tumor load”, refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • tumor size refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.
  • imaging techniques e.g., bone scan, ultrasound, CT or MRI scans.
  • Unidimensional irRC refers to the set of criteria described in Nishino M, Giobbie- Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a Common Language for Tumor Response to Immunotherapy: Immune-related Response Criteria using Unidimensional measurements. Clin Cancer Res. 2013; 19(14):3936- 3943). These criteria utilize the longest diameter (cm) of each lesion.
  • Neoadjuvant refers to the treatment (e.g., combination therapy comprising the PD-1 antagonist and LAG3 antagonist) before surgical resection of a tumor in the patient.
  • V region means the segment of IgG chains which is variable in sequence between different antibodies. Typically, it extends to Kabat residue 109 in the light chain and 113 in the heavy chain.
  • Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the treatment methods, combinations, pharmaceutical compositions, medicaments and uses of the present invention include :pembrolizumab (also known as MK-3475), a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and that comprises the heavy and light chain amino acid sequences shown in Table 3; nivolumab (BMS-936558), a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No.
  • mAbs that bind to human PD-L1 are described in US8383796.
  • Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment methods, combinations, pharmaceutical compositions, medicaments and uses of the present invention include BMS-936559, MEDI4736, and MSB0010718C.
  • PD-1 antagonists useful in the treatment methods, combinations, pharmaceutical compositions, medicaments and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that comprises: (a) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 1, 2 and 3, respectively and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8, respectively.
  • the PD-1 antagonist is a humanized antibody.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising SEQ ID NO:9 or a variant thereof, and (b) a light chain variable region comprising SEQ ID NO:4 or a variant thereof.
  • a variant of a heavy chain variable region sequence is identical to the reference sequence except having up to six conservative amino acid substitutions in the framework region (i.e., outside of the CDRs).
  • a variant of a light chain variable region sequence is identical to the reference sequence except having up to three conservative amino acid substitutions in the framework region (i.e., outside of the CDRs).
  • the PD-1 antagonist is an anti-PD-1 antibody that comprises two heavy chains and two light chains, and wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises SEQ ID NO:5.
  • the PD-1 antagonist is pembrolizumab.
  • the PD-1 antagonist is a pembrolizumab variant.
  • the PD-1 antagonist is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a heavy chain comprising SEQ ID NO: 12 and (b) a light chain comprising SEQ ID NO: 11.
  • the PD-1 antagonist is nivolumab.
  • the PD-1 antagonist inhibits the binding of PD-L1 to PD-1, and preferably also inhibits the binding of PD-L2 to PD-1.
  • the PD- 1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof, that specifically binds to PD-1 or to PD-L1 and blocks the binding of PD-L1 to PD-1.
  • Table 3 provides a list of the amino acid sequences of exemplary anti-PD-1 mAbs for use in the treatment methods, combinations, pharmaceutical compositions, medicaments and uses of the present invention.
  • LAG3 antagonists useful in the treatment methods, combinations, pharmaceutical compositions, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, that specifically binds to LAG3.
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgGl or IgG4 constant region.
  • the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
  • the anti-LAG3 antibody is bootszelimab.
  • Favezelimab light chain immunoglobulin variable domain amino acid sequence DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDR FSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIK (SEQ ID NO: 24); and
  • Favezelimab heavy chain immunoglobulin variable domain amino acid sequence QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQK FQERVTITVDKSTSTAYMELS SLRSEDTA VYYCARNYRWFGAMDHWGQGTTVTVS S (SEQ ID NO: 25).
  • CDR-L1 KASQSLDYEGDSDMN (SEQ ID NO: 26);
  • CDR-L2 GASNLES (SEQ ID NO: 27);
  • CDR-L3 QQSTEDPRT (SEQ ID NO: 28);
  • CDR-H1 DYNVD (SEQ ID NO: 29);
  • CDR-H2 DINPNDGGTIYAQKFQE (SEQ ID NO: 30);
  • the LAG3 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that comprises: (a) light chain CDR1, CDR2 and CDR3 amino acid sequences in SEQ ID NOs: 26, 27 and 28 and (b) heavy chain CDR1, CDR2 and CDR3 amino acid sequences in SEQ ID NOs: 29, 30 and 31.
  • the LAG3 antagonist is relatlimab. In another embodiment, the LAG3 antagonist is fianlimab.
  • Other LAG3 antagonists useful in the treatment methods, combinations, pharmaceutical compositions, medicaments and uses of the present invention include an immunoadhesin that specifically binds to human LAG3, e.g., a fusion protein containing the extracellular LAG3 fused to a constant region such as an Fc region of an immunoglobulin molecule.
  • each of the anti-PD-1 or anti-LAG3 antibodies or antigen-binding fragments thereof comprises a heavy chain constant region, e.g. a human constant region, such as yl, y2, y3, or y4 human heavy chain constant region or a variant thereof.
  • each of the anti-PD-1 or anti-LAG3 antibodies or antigen-binding fragments thereof comprises a light chain constant region, e.g. a human light chain constant region, such as lambda or kappa human light chain region or a variant thereof.
  • the human heavy chain constant region can be y4 and the human light chain constant region can be kappa.
  • the Fc region of the antibody is y4 with a Ser228Pro mutation (Schuurman, J et. al. , Mol. Immunol. 38: 1-8, 2001).
  • different constant domains may be appended to humanized VL and VH regions derived from the CDRs provided herein.
  • a heavy chain constant domain other than human IgGl may be used, or hybrid IgGl/IgG4 may be utilized.
  • the invention provides a medicament comprising a PD-1 antagonist for use in combination with a LAG3 antagonist for treating cancer before and/or after surgical resection of a tumor.
  • the invention provides a medicament comprising a LAG3 antagonist for use in combination with a PD-1 antagonist for treating cancer before and/or after surgical resection of a tumor.
  • the invention provides for the use of a PD-1 antagonist in the manufacture of a medicament for treating cancer in an individual when administered in combination with a LAG3 antagonist before and/or after surgical resection of a tumor.
  • the invention provides for the use of a LAG3 antagonist in the manufacture of a medicament for treating cancer in an individual when administered in combination with a PD-1 antagonist before and/or after surgical resection of a tumor.
  • the invention provides the use of a PD-1 antagonist and a LAG3 antagonist in the manufacture of a medicament for treating cancer before and/or after surgical resection of a tumor.
  • LAG3 antagonists for use in the treatment of cancer, wherein the use is in combination with a PD-1 antagonist before and/or after surgical resection of a tumor; a PD-1 antagonist for use in the treatment of cancer, wherein the use is in combination with a LAG3 antagonist before and/or after surgical resection of a tumor; a PD-1 antagonist and LAG3 antagonist for use in the treatment of cancer, wherein the use is before and/or after surgical resection of a tumor.
  • the PD-1 antagonist and LAG3 antagonist are administered before surgical resection of a tumor, and optionally followed by treatment with a PD-1 antagonist after surgery.
  • the PD-1 antagonist and LAG3 antagonist are administered after surgical resection of a tumor, and optionally a PD-1 antagonist is administered before surgery.
  • the PD-1 antagonist and LAG3 antagonist are administered before and after surgical resection of a tumor.
  • the PD-1 antagonist is pembrolizumab and the LAG3 antagonist is favezelimab.
  • the PD-1 antagonist is nivolumab and the LAG3 antagonist is relatlimab.
  • the PD-1 antagonist is cemiplimab and the LAG3 antagonist is fianlimab.
  • combinations, pharmaceutical compositions, medicaments and uses comprises administering via intravenous infusion to the human individual a composition comprising 200 mg of pembrolizumab and 800 mg of favezelimab every 3 weeks before and after surgical resection.
  • Cancers that may be treated by the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention include, but are not limited to: Cardiac cancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung cancers: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancers: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphom
  • the forgoing cancers are resectable.
  • the cancer is Stage IV.
  • the cancer is Stage III.
  • the cancer is Stage II.
  • the cancer is Stage I.
  • the cancer is without distant metastasis.
  • the cancer is stage I, II, III or IV without distant metastasis.
  • cancers that may be treated by the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention include, but are not limited to: cutaneous squamous cell carcinoma, melanoma, breast cancer, non-small cell lung cancer, bladder cancer, esophageal cancer, renal cell cancer, endometrial cancer and colorectal cancer.
  • the colorectal cancer or endometrial cancer is non-microsatellite instability- high (non-MSI-H) or proficient mismatch repair (pMMR).
  • the cancer is microsatellite instability-high (MSI-H) colorectal cancer.
  • the colorectal cancer is non-microsatellite instability-high (non-MSI-H) or proficient mismatch repair (pMMR).
  • the cancer is renal cell carcinoma.
  • the cancer is clear cell renal cell carcinoma.
  • the cancer is resectable.
  • the cancer is Stage IV.
  • the cancer is Stage III.
  • the cancer is Stage II.
  • the cancer is Stage I.
  • the cancer is without distant metastasis.
  • the cancer is stage I, II, III or IV without distant metastasis.
  • the cancer is cutaneous squamous cell carcinoma.
  • the cancer is melanoma.
  • the cancer is triple negative breast cancer.
  • the cancer is Her2 positive breast cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is non-muscle invasive bladder cancer.
  • the cancer is resectable.
  • the cancer is Stage IV.
  • the cancer is Stage III. In one embodiment, the cancer is Stage II. In one embodiment, the cancer is Stage I. In another embodiment, the cancer is without distant metastasis. In another embodiment, the cancer is stage I, II, III or IV without distant metastasis. In another embodiment, the cancer is cutaneous squamous carcinoma at stage II, III or IV. In another embodiment, the cancer is cutaneous squamous carcinoma at stage I, II, III or IV. In another embodiment, the cancer is cutaneous squamous carcinoma at stage II, III or IV without distant metastasis. In another embodiment, the cancer is cutaneous squamous carcinoma at stage I, IT, TIT or TV without distant metastasis.
  • a combination therapy of the invention is typically used to treat a tumor that is large enough to be found by palpation or by imaging techniques well known in the art, such as MRI, ultrasound, or CAT scan, and is resectable by surgery.
  • the patient with cancer progressed after anti-PD-1 or anti-PD-Ll treatment.
  • the patient with cancer has not received prior anti-PD-1 or anti-PD-Ll treatment.
  • the patient with cancer has not received prior immunotherapy treatment.
  • the patient with cancer has not received prior systemic therapy treatment.
  • the patient has not been previously treated with chemotherapy or an EGFR inhibitor such as cetuximab or panitumumab.
  • the combination therapy of the PD-1 antagonist and LAG3 antagonist is for first line treatment.
  • the combination therapy of the PD-1 antagonist and LAG3 antagonist is for second or third line treatment.
  • a combination therapy of the invention is administered to a patient who has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naive.
  • the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
  • the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention may also comprise one or more additional therapeutic agents.
  • the additional therapeutic agent may be, e.g., a chemotherapeutic, a biotherapeutic agent, an immunogenic agent (for example, attenuated cancerous cells, tumor antigens, antigen presenting cells such as dendritic cells pulsed with tumor derived antigen or nucleic acids, immune stimulating cytokines (for example, IL-2, IFNa2, GM-CSF), and cells transfected with genes encoding immune stimulating cytokines such as but not limited to GM-CSF).
  • the specific dosage and dosing schedule of the additional therapeutic agent can further vary, and the optimal dose, dosing schedule and route of administration will be determined based upon the specific therapeutic agent that is being used.
  • Each therapeutic agent in the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention may be administered either alone or in a medicament (also referred to herein as a pharmaceutical composition) that comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents, according to standard pharmaceutical practice.
  • Each therapeutic agent in the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order.
  • Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a chemotherapeutic that is administered at least daily and a biotherapeutic that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks.
  • the LAG3 antagonist is administered before administration of the PD-1 antagonist, while in other embodiments, the LAG3 antagonist is administered after administration of the PD-1 antagonist. In another embodiment, the LAG3 antagonist is administered concurrently with the PD-1 antagonist.
  • At least one of the therapeutic agents in the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same cancer.
  • the patient receives a lower total amount of at least one of the therapeutic agents in the methods, combinations, pharmaceutical compositions, medicaments and uses than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.
  • Each small molecule therapeutic agent in the methods, combinations, pharmaceutical compositions, medicaments and uses of the invention can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration.
  • a combination therapy of the invention can be administered to a human patient who has a cancer that tests positive for one or both of PD-L1 and PD-L2, and preferably tests positive for PD-L1 expression.
  • PD-L1 expression is detected using a diagnostic anti-human PD-L1 antibody, or antigen binding fragment thereof, in an IHC assay on an FFPE or frozen tissue section of a tumor sample removed from the patient.
  • the patient’s physician would order a diagnostic test to determine PD-L1 expression in a tumor tissue sample removed from the patient prior to initiation of treatment with the PD-1 antagonist, the LAG3 antagonist but it is envisioned that the physician could order the first or subsequent diagnostic tests at any time after initiation of treatment, such as for example after completion of a treatment cycle.
  • the PD-L1 expression is measured by the PD-L1 IHC 22C3 pharmDx assay.
  • the PD-L1 expression is measured by immunohistochemistry detection in formalin-fixed, paraffin-embedded tumor tissue sections using an anti-PD-Ll antibody comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 21 and light chain variable region amino acid sequence of SEQ ID NO: 16.
  • the patient has a Mononuclear Inflammatory Density Score for PD-L1 expression >2.
  • the patient has a Mononuclear Inflammatory Density Score for PD-L1 expression >3.
  • the patient has a Mononuclear Inflammatory Density Score for PD-L1 expression >4.
  • Tumor Proportion Score for PD-L1 expression is used for selection of non-small cell lung cancer patients.
  • the patient has a Tumor Proportion Score for PD-L1 expression >1%.
  • the patient has a Tumor Proportion Score for PD-L1 expression >10%.
  • the patient has a Tumor Proportion Score for PD-L1 expression >20%.
  • the patient has a Tumor Proportion Score for PD-L1 expression >30%.
  • the patient has a Tumor Proportion Score for PD-L1 expression >50%.
  • the patient has a Combined Positive Score for PD-L1 expression >1%.
  • the patient has a Combined Positive Score for PD-L1 expression between 1 and 20 %. In a further embodiment, the patient has a Combined Positive Score for PD-L1 expression > 2%. In a further embodiment, the patient has a Combined Positive Score for PD-L1 expression > 5%. In yet a further embodiment, the patient has a Combined Positive Score for PD-L1 expression > 10%. In a further embodiment, the patient has a Combined Positive Score for PD-L1 expression > 15%. In yet a further embodiment, the patient has a Combined Positive Score for PD-L1 expression > 20%.
  • a dosage regimen for a combination therapy of the invention depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the individual being treated.
  • a dosage regimen maximizes the amount of each therapeutic agent delivered to the patient consistent with an acceptable level of side effects.
  • the dose amount and dosing frequency of each biotherapeutic and chemotherapeutic agent in the combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and patient characteristics. Guidance in selecting appropriate doses of antibodies, cytokines, and small molecules are available.
  • Determination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and will depend, for example, the patient's clinical history (e g., previous therapy), the type and stage of the cancer to be treated and biomarkers of response to one or more of the therapeutic agents in the combination therapy.
  • Biotherapeutic agents in a combination therapy of the invention may be administered by continuous infusion, or by doses at intervals of, e.g., daily, every other day, three times per week, or one time each week, two weeks, three weeks, monthly, bimonthly, etc.
  • a total weekly dose is generally at least 0.05 pg/kg, 0.2 pg/kg, 0.5 pg/kg, 1 pg/kg, 10 pg/kg, 100 pg/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med.
  • the dosing regimen will comprise administering the anti-human PD-1 mAh at a dose of 1, 2, 3, 5 or lOmg/kg at intervals of about 14 days ( ⁇ 2 days) or about 21 days ( ⁇ 2 days) or about 30 days ( ⁇ 2 days) throughout the course of treatment.
  • the dosing regimen will comprise administering the anti-human PD-1 mAb at a dose of from about 0.005 mg/kg to about 10 mg/kg, with intra-patient dose escalation.
  • the interval between doses will be progressively shortened, e g., about 30 days ( ⁇ 2 days) between the first and second dose, about 14 days ( ⁇ 2 days) between the second and third doses.
  • the dosing interval will be about 14 days ( ⁇ 2 days), for doses subsequent to the second dose.
  • a subject will be administered an intravenous (IV) infusion or subcutaneous injection of a medicament comprising any of the PD-1 antagonists described herein.
  • IV intravenous
  • the PD-1 antagonist in the combination therapy is nivolumab, which is administered intravenously at a dose selected from the group consisting of: 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, and 10 mg/kg Q3W.
  • the PD-1 antagonist in the combination therapy is pembrolizumab, or a pembrolizumab variant, that is administered in a liquid medicament at a dose selected from the group consisting of 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg/kg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, 10 mg/kg Q3W and flat-dose equivalents of any of these doses, i.e., such as 200 mg Q3W or 400 mg Q6W.
  • a dose selected from the group consisting of 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg/kg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, 10 mg/kg Q3W and flat-dose
  • pembrolizumab is provided as a liquid medicament that comprises 25 mg/ml pembrolizumab, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5.
  • pembrolizumab is provided as a liquid medicament that comprises about 125 to about 200 mg/mL of pembrolizumab, or an antigen binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof; about 7% (w/v) sucrose; and about 0.02 % (w/v) polysorbate 80.
  • the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes. In other embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection. [0134] In one aspect of the invention, the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist before and optionally after surgical resection of a tumor. In one embodiment, the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for one to five treatment cycles before surgical resection of a tumor, e.g., one to five 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for one to four treatment cycles before surgical resection of a tumor, e.g., one to four 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for one to three treatment cycles before surgical resection of a tumor, e.g., one to three 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for one to two treatment cycles before surgical resection of a tumor, e.g., one to two 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for 1 treatment cycle before surgical resection of a tumor, e.g., one 3-week cycle.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for five treatment cycles before surgical resection of a tumor, e.g., five 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for four treatment cycles before surgical resection of a tumor, e.g., four 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for three treatment cycles before surgical resection of a tumor, e.g., three 3- week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for two treatment cycles before surgical resection of a tumor, e.g., two 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for 1 treatment cycle before surgical resection of a tumor, e.g., one 3-week cycle.
  • the surgical resection can take place any time after completion of a treatment cycle of the combination therapy of the PD-1 antagonist and LAG3 antagonist. In one embodiment, the surgical resection is performed within 12 weeks of first administration of the PD-1 antagonist and LAG3 antagonist. In one embodiment, the surgical resection is performed within 18 weeks of first administration of the combination therapy of the PD-1 antagonist and LAG3 antagonist. In one embodiment, the surgical resection is performed within 14 weeks of first administration of the combination therapy of the PD-1 antagonist and LAG3 antagonist.
  • re-resection is performed before adjuvant administration of the PD-1 antagonist and LAG3 antagonist.
  • a second surgical resection of the tumor is performed before administration of the anti-PD-1 antibody and anti-LAG3 antibody.
  • patients After surgical resection (or re-resection) of the tumor, if margins are still positive on pathology, in one embodiment, patients receive adjuvant radiation therapy prior to receiving adjuvant administration of the PD-1 antagonist and LAG3 antagonist.
  • radiation therapy is administered before administration of the anti-PD-1 antibody and anti-LAG3 antibody.
  • the anti-PD-1 antibody and anti-LAG3 antibody administration starts at least 4 weeks and up to 12 weeks after surgical resection or last dose of radiation therapy.
  • adjuvant radiation therapy is administered for one to six weeks. In one embodiment, adjuvant radiation therapy is administered for six weeks for a total of 60 to 70 Gy. In one embodiment, adjuvant radiation therapy is administered for three to four weeks for a total of 45 to 50 Gy.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for one to eighteen treatment cycles after surgical resection of a tumor, e g., one to eighteen 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for one to fourteen treatment cycles after surgical resection of a tumor, e.g., one to fourteen 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for fourteen treatment cycles after surgical resection of a tumor, e.g., fourteen 3-week cycles.
  • the combination therapy of the PD-1 antagonist and LAG3 antagonist is administered at a total of seventeen treatment (3-week) cycles before and after surgical resection of the tumor. In a further embodiment, the combination therapy of the PD-1 antagonist and LAG3 antagonist is administered at a total of eighteen treatment (3-week) cycles before and after surgical resection of the tumor.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for eighteen treatment cycles after surgical resection of a tumor, e.g., eighteen 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for seventeen treatment cycles after surgical resection of a tumor, e.g., seventeen 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for sixteen treatment cycles after surgical resection of a tumor, e.g., sixteen 3-week cycles.
  • the patient is treated with the combination therapy of the PD-1 antagonist and LAG3 antagonist for fifteen treatment cycles after surgical resection of a tumor, e.g., fifteen 3-week cycles.
  • the anti-PD-1 or anti-PD-Ll antibody and anti-LAG3 antibody are co-formulated.
  • the invention provides a method for treating cancer in a patient comprising administering via intravenous infusion to the individual a composition comprising 200 mg of pembrolizumab or pembrolizumab variant and 800 mg of favezelimab or bootszelimab variant on Day 1 every three weeks for one to three treatment cycles before surgical resection of the tumor, and one to fourteen treatment cycles after surgery.
  • the invention provides a method for treating cancer in a patient comprising administering via intravenous infusion to the individual a composition comprising 200 mg of pembrolizumab and 800 mg of favezelimab on Day 1 every three weeks for one to three treatment cycles before surgical resection of the tumor, and one to fourteen treatment cycles after surgery.
  • the invention provides a method for treating cancer in a patient comprising administering via intravenous infusion to the individual a composition comprising 200 mg of pembrolizumab or pembrolizumab variant and 800 mg of favezelimab or favezelimab variant on Day 1 every three weeks for one to four treatment cycles before surgical resection of the tumor, and one to fourteen treatment cycles after surgery.
  • the invention provides a method for treating cancer in a patient comprising administering via intravenous infusion to the individual a composition comprising 200 mg of pembrolizumab and 800 mg of favezelimab on Day 1 every three weeks for one to four treatment cycles before surgical resection of the tumor, and one to fourteen treatment cycles after surgery.
  • the anti-PD-1 or anti-PD-Ll antibody and anti-LAG3 antibody are co-administered.
  • 200 mg pembrolizumab or pembrolizumab variant and 800 mg Favezelimab or Favezelimab variant are co-administered on Day 1 every three weeks for intravenous infusion for one to three treatment cycles before surgical resection of the tumor, and one to fourteen treatment cycles after surgery.
  • the anti-PD-1 antibody and anti-LAG3 antibody are administered before surgical resection of a tumor, and followed by treatment with an anti-PD-1 antibody after surgery.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 14 treatment cycles after surgical resection.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 18 treatment cycles after surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 17 treatment cycles after surgical resection.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 16 treatment cycles after surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 14 treatment cycles after surgical resection.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 13 treatment cycles after surgical resection.
  • the anti-PD-1 antibody and anti-LAG3 antibody are administered before surgical resection of a tumor, and followed by treatment with an anti-PD-1 antibody after surgery.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 14 treatment cycles after surgical resection.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 18 treatment cycles after surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 17 treatment cycles after surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 16 treatment cycles after surgical resection.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 14 treatment cycles after surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 13 treatment cycles after surgical resection.
  • the anti-PD-1 antibody and anti-LAG3 antibody are administered after surgical resection of a tumor, and an anti-PD-1 antibody is administered before surgery.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 4 treatment cycles before surgical resection.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 to 3 treatment cycles before surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab or pembrolizumab variant every 3 weeks or 400 mg of pembrolizumab or pembrolizumab variant every six weeks for 1 treatment cycle before surgical resection.
  • the anti-PD-1 antibody and anti-LAG3 antibody are administered after surgical resection of a tumor, and an anti-PD-1 antibody is administered before surgery.
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to
  • the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 3 treatment cycles before surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 to 2 treatment cycles before surgical resection. In one embodiment, the method comprises administering via intravenous infusion to the individual 200 mg of pembrolizumab every 3 weeks or 400 mg of pembrolizumab every six weeks for 1 treatment cycle before surgical resection.
  • compositions of the present disclosure include for instance, solvents, bulking agents, buffering agents, tonicity adjusting agents, and preservatives (see, e.g., Pramanick et al., Pharma Times, 45:65-77, 2013).
  • the pharmaceutical compositions may comprise an excipient that functions as one or more of a solvent, a bulking agent, a buffering agent, and a tonicity adjusting agent (e.g., sodium chloride in saline may serve as both an aqueous vehicle and a tonicity adjusting agent).
  • the pharmaceutical compositions comprise an aqueous vehicle as a solvent. Suitable vehicles include for instance sterile water, saline solution, phosphate buffered saline, and Ringer's solution.
  • the composition is isotonic.
  • the pharmaceutical compositions may comprise a bulking agent.
  • Bulking agents are particularly useful when the pharmaceutical composition is to be lyophilized before administration.
  • the bulking agent is a protectant that aids in the stabilization and prevention of degradation of the active agents during freeze or spray drying and/or during storage.
  • Suitable bulking agents are sugars (mono-, di- and polysaccharides) such as sucrose, lactose, trehalose, mannitol, sorbital, glucose and raffinose.
  • the pharmaceutical compositions may comprise a buffering agent.
  • Buffering agents control pH to inhibit degradation of the active agent during processing, storage and optionally reconstitution.
  • Suitable buffers include for instance salts comprising acetate, citrate, phosphate or sulfate.
  • Other suitable buffers include for instance amino acids such as arginine, glycine, histidine, and lysine.
  • the buffering agent may further comprise hydrochloric acid or sodium hydroxide.
  • the buffering agent maintains the pH of the composition within a range of 4 to 9.
  • the pH is greater than (lower limit) 4, 5, 6, 7 or 8.
  • the pH is less than (upper limit) 9, 8, 7, 6 or 5. That is, the pH is in the range of from about 4 to 9 in which the lower limit is less than the upper limit.
  • the pharmaceutical compositions may comprise a tonicity adjusting agent.
  • Suitable tonicity adjusting agents include for instance dextrose, glycerol, sodium chloride, glycerin and mannitol.
  • the pharmaceutical compositions may comprise a preservative. Suitable preservatives include for instance antioxidants and antimicrobial agents. However, in preferred embodiments, the pharmaceutical composition is prepared under sterile conditions and is in a single use container, and thus does not necessitate inclusion of a preservative.
  • a medicament comprising an anti-PD-1 antibody as the PD-1 antagonist may be provided as a liquid formulation or prepared by reconstituting a lyophilized powder with sterile water for injection prior to use.
  • PCT International application publ. no. WO 2012/135408 describes the preparation of liquid and lyophilized medicaments comprising pembrolizumab that are suitable for use in the present invention.
  • a medicament comprising pembrolizumab is provided in a glass vial that contains about 100 mg of pembrolizumab in 4 ml of solution.
  • Each 1 mb of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.
  • L-histidine (1.55 mg
  • polysorbate 80 0.2 mg
  • sucrose 70 mg
  • Water for Injection USP.
  • the solution requires dilution for IV infusion.
  • a medicament comprising an anti-LAG3 antibody as the LAG3 antagonist may be provided as a liquid formulation or prepared by reconstituting a lyophilized powder with sterile water for injection prior to use.
  • the liquid formulation comprises about 25 mg/mL anti-LAG3 antibody; about 50 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM L-histidine buffer at about pH 5.8-6.0; about 70 mM L-Arginine- HC1 thereof; and optionally about 10 mM L-methionine.
  • the medicament is a co-formulation of an anti-LAG3 antibody or antigen binding fragment and an anti-PD-1 antibody or antigen binding fragment with 20 mg/mL of Favezelimab or Favezelimab variant, 5 mg/mL or pembrolizumab or pembrolizumab variant, 56 mM L-Arginine HC1, 5.4% sucrose, 8.0 mM methionine, 0.02% PS-80, and 10 mM Histidine buffer.
  • the medicaments described herein may be provided as a kit that comprises a first container, a second container and a package insert or label.
  • the medicaments described herein may also be provided as a kit which comprises a first container, a second container, and a package insert or label.
  • the first container contains at least one dose of a medicament comprising a PD-1 antagonist and at least one dose of a medicament comprising a LAG3 antagonist, and the package insert or label, that comprises instructions for treating a patient for cancer using the medicaments.
  • the first and second containers may be comprised of the same or different shapes (e.g., vials, syringes and bottles) and/or material (e.g., plastic or glass).
  • the kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes.
  • the PD-1 antagonist is an anti-PD-1 antibody and the instructions state that the medicaments are intended for use in treating a patient having cancer that tests positive for PD-L1 expression by an IHC assay.
  • Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer- Verlag, New York;
  • An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309- 314; Barbas (1995) Nature Medicine 1 :837-839; Mendez et al. (1997) Nature Genetics 15: 146- 156; Hoogenboom and Chames (2000) Immunol. Today 21 :371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New Y ork; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).
  • Antibodies can be conjugated, e.g., to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g., colloidal gold (see, e.g., Le Doussal et al. (1991) J. Immunol. 146: 169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811;
  • Fluorescent reagents suitable for modifying nucleic acids including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).
  • Example 1 Clinical Studies of favezelimab-pembrolizumab co-formulation before (neoadjuvant) and after surgical resection (adjuvant)
  • Participants will receive treatment with favezelimab-pembrolizumab or pembrolizumab for up to 14 cycles of adjuvant therapy, starting at least 4 weeks and up to 12 weeks after surgery (or last dose of radiation therapy (RT) if the participant undergoes RT). Participants will undergo first post-surgical imaging assessment at A1D1 (+7 days). Subsequent tumor imaging should be performed Q12W (84 days +/- 7 days) from A1D1 for up to 1 year, or more frequently if clinically indicated, or until documented disease recurrence.
  • Cohort A Each participant will be randomly assigned to receive either favezelimab- pembrolizumab or pembrolizumab for up to 3 cycles of neoadjuvant therapy. After surgical resection of the tumor, participants will continue study intervention with favezelimab- pembrolizumab or pembrolizumab up to 14 cycles of adjuvant therapy.
  • pCR is a clinically meaningful endpoint regardless of impacts on events and survival, and, based on very high expected pCR rate, is also a potentially appropriate surrogate for EFS.
  • a challenge of using pCR as a surrogate for OS/EFS is the relatively low pCR rate after neoadjuvant therapy in most tumors. For example, in breast cancer the pCR ranges between 13-22%. With most patients not achieving a pCR, providing correlation with OS/EFS is difficult in an intention- to-treat population. However, the pCR rate for cSCC is expected to be significantly higher (greater than 50%) and, therefore, expected to have a strong correlation with improvement in OS/EFS.
  • Secondary endpoints for Cohort A include: EFS based on RECIST 1.1 criteria as assessed by investigator; mPR as assessed by blinded central pathology review; OR based on RECIST 1.1 criteria as assessed by investigator; and pCR or cCR with negative biopsy.
  • EFS is a common surrogate endpoint for OS that is used to evaluate the efficacy of neoadjuvant and adjuvant cancer therapy and is sometimes used as primary endpoint.
  • the favezelimab-pembrolizumab combination therapy has the potential to further reduce tumor volume, increase pCR rates and improve event-free survival.

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Abstract

La présente divulgation concerne des polythérapies faisant appel à un antagoniste du récepteur de mort programmée 1 (PD-1) et un antagoniste du gène 3 d'activation des lymphocytes (LAG3), pour le traitement du cancer avant et/ou après chirurgie.
PCT/US2024/044966 2023-09-07 2024-09-03 Polythérapie à base d'un antagoniste de pd-1 et d'un antagoniste de lag3 pour le traitement de patients atteints d'un cancer avant et/ou après chirurgie Pending WO2025054110A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014193898A1 (fr) * 2013-05-31 2014-12-04 Merck Sharp & Dohme Corp. Thérapies combinées contre le cancer
WO2016028672A1 (fr) * 2014-08-19 2016-02-25 Merck Sharp & Dohme Corp. Anticorps et fragments de fixation à l'antigène anti-lag3
WO2022146947A1 (fr) * 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Compositions d'anticorps et leurs procédés d'utilisation
WO2022173931A1 (fr) * 2021-02-11 2022-08-18 Regeneron Pharmaceuticals, Inc. Méthodes de traitement du cancer par administration d'un inhibiteur de pd-1 néoadjuvant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014193898A1 (fr) * 2013-05-31 2014-12-04 Merck Sharp & Dohme Corp. Thérapies combinées contre le cancer
WO2016028672A1 (fr) * 2014-08-19 2016-02-25 Merck Sharp & Dohme Corp. Anticorps et fragments de fixation à l'antigène anti-lag3
WO2022146947A1 (fr) * 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Compositions d'anticorps et leurs procédés d'utilisation
WO2022173931A1 (fr) * 2021-02-11 2022-08-18 Regeneron Pharmaceuticals, Inc. Méthodes de traitement du cancer par administration d'un inhibiteur de pd-1 néoadjuvant

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