WO2022266496A1 - Procédés de traitement de sous-types de mutation kras avec un agoniste cd40 - Google Patents

Procédés de traitement de sous-types de mutation kras avec un agoniste cd40 Download PDF

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WO2022266496A1
WO2022266496A1 PCT/US2022/034080 US2022034080W WO2022266496A1 WO 2022266496 A1 WO2022266496 A1 WO 2022266496A1 US 2022034080 W US2022034080 W US 2022034080W WO 2022266496 A1 WO2022266496 A1 WO 2022266496A1
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cancer
antibody
subject
inhibitors
agonist
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Lacey KITCH
Theresa Lavallee
Lee Davis MCDANIEL
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Parker Institute For Cancer Immunotherapy
Personalis, Inc.
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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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—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
    • 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
    • C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • pancreatic cancer While it is well known the majority of pancreatic cancer has mutations in, for example, KRAS, p53 and SMAD4, these biomarkers have only shown to be associated with worse prognosis. As reported in The Cancer Genomic Atlas (TCGA) database, a hallmark of pancreatic cancer is the prevalence of oncogenic mutation in the KRAS gene. [0003] With substantial experimental evidence that mutant KRAS is essential for e.g., pancreatic ductal adenocarcinoma (PDAC) growth, the National Cancer Institute identified targeting KRAS as one of four major priorities for pancreatic cancer research. The current standards of care for PDAC consist of conventional cytotoxic drugs.
  • PDAC pancreatic ductal adenocarcinoma
  • a method of aiding a treatment of a subject with cancer comprising: (a) determining a KRAS mutation subtype of a biological sample obtained from the subject; and (b) aiding the treatment of the subject with a combination a CD40 agonist and chemotherapy, wherein the KRAS mutation subtype is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • a method for treating a subject with cancer comprising: (a) determining a KRAS mutation subtype of a biological sample obtained from the subject; and (b) treating the subject with a combination of a CD40 agonist and chemotherapy, wherein the KRAS mutation subtype is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • a method for treating a subject with cancer comprising: (a) determining sorting nexin 19 (SNX19) expression level of a test biological sample and one or more reference biological samples, wherein a reference biological sample of the one or more reference biological samples is collected from each individual among a cohort of subjects having the same cancer, wherein the subject is part of the cohort; (b) calculating a SNX19 expression score of the subject; and (c) treating the subject with a combination of a CD40 agonist and chemotherapy, wherein the SNX expression score of the subject is high as compared to a median SNX19 expression score of the cohort.
  • SNX19 sorting nexin 19
  • step (a) optionally comprises determining a KRAS mutation subtype of the subject.
  • the KRAS mutation subtype is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • the amino acid N is selected from the group consisting of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamine (Q), glutamic acid (E), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), and valine (V).
  • the amino acid N is aspartic acid (D).
  • the CD40 agonist is selected from the group consisting of an anti-CD40 antibody or antigen binding fragment thereof, a CD40L fragment, a CD40 ligand fusion protein, and a CD40L mimetic. In some embodiments, the CD40 agonist is the anti-CD40 antibody or antigen binding fragment thereof.
  • the anti-CD40 antibody or antigen binding fragment thereof is a camelized single domain antibody, a diabody, a scFv, an scFv dimer, a BsFv, a dsFv, a (dsFv) 2 , a dsFv-dsFv’, an Fv fragment, a Fab, a Fab’, a F(ab’)2, a ds diabody, a nanobody, a domain antibody, or a bivalent domain antibody.
  • the anti-CD40 antibody or antigen binding fragment thereof is selected from the group consisting of sotigalimab (APX005M), selicrelumab, ChiLob7/4. mitazalimab (ADC-1013), SEA-CD40, CP-870,893, dacetuzumab, SGN-40, CDX-1140, and giloralimab (ABBV-927).
  • the anti-CD40 antibody is sotigalimab.
  • the CD40 ligand fusion protein is HERA-CD40L or MDI5083.
  • the additional therapy is selected from the group consisting of a PD-(L)1 inhibitor, a kinase inhibitor, a cancer vaccine, radiotherapy, stem cell therapy, surgery, gene therapy, or other biologics.
  • the additional therapy is the PD-(L)1 inhibitor.
  • the PD-(L)1 inhibitor is an anti-PD-1 antibody or antigen binding fragment thereof.
  • the anti-PD-(L)1 antibody or antigen binding fragment thereof is selected from the group consisting of nivolumab, toripalimab, sintilimab, camrelizumab, zimberelimab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostarlimab, JTX-4014, spartalizumab, tislelizumab, AMP-224, AMP- 514, INCMGA00012, KN035, CK-301, AUNP12, CA-170, and BMS-986189.
  • the anti-PD-(L)1 antibody is nivolumab.
  • the chemotherapy is selected from the group consisting of gemcitabine, nab-paclitaxel, folfirionx, nitrogen mustard / oxazaphosphorine, nitrosourea, triazene, and alkyl sulfonates, anthracycline antibiotics such as doxorubicin and daunorubicin, taxanes such as Taxol brand and docetaxel, vinca alkaloids such as vincristine and vinblastine, 5- fluorouracil (5-FU), leucovorin, Irinotecan, idarubicin, mitomycin C, oxaliplatin, raltitrexed, pemetrexed, tamoxifen, cisplatin, carboplatin, methotrexate, a Tinomycin D, mitoxantrone, brenoxane, mitra
  • the chemotherapy is a combination of gemcitabine and nab-paclitaxel.
  • the cancer is selected from the group consisting of a pancreatic cancer, an endometrial cancer, a non-small cell lung cancer (NSCLC), a renal cell carcinoma, a urothelial cancer, a head and neck cancer, a melanoma, a bladder cancer, a hepatocellular carcinoma, a breast cancer, an ovarian cancer, a gastric cancer, a colorectal cancer, a glioblastoma, a biliary tract cancer, a glioma, Merkel cell carcinoma, Hodgkin lymphoma, non- Hodgkin lymphoma, a cervical cancer, an advanced or refractory solid tumor, a small cell lung cancer, a non-squamous non-small cell lung cancer, desmoplastic melanoma, a pediatric advanced solid tumor or lymphoma, a mes
  • the cancer is a pancreatic cancer.
  • the pancreatic cancer is pancreatic ductal adenocarcinoma.
  • the biological sample is a tumor sample.
  • the biological sample is a blood sample.
  • the treatment improves overall survival (OS) of the subject.
  • OS overall survival
  • FIG.1A shows immune profiling of peripheral blood mononuclear cells (PBMCs), showing an increase in activated effector memory (EM) T cells (Ki67 + CD8 + ) in all three cohorts, with cohort A1 (nivolumab + chemotherapy) showing the most pronounced effect.
  • FIG.1B shows immune profiling of peripheral blood mononuclear cells (PBMCs), showing an increase in activated myeloid dendritic cells (CD86 + mDC) in cohort B2 and C2.
  • PBMCs peripheral blood mononuclear cells
  • CD86 + mDC activated myeloid dendritic cells
  • FIG.2A shows tumor multiplex IHC analyses of all three cohorts, showing a decrease in the percentage of tumor cells expressing PD-L1 in cohorts A1 and C2, while cohort B2 showed mixed changes in PD-L1 expression.
  • FIG.2B shows tumor multiplex IHC analyses of all three cohorts, showing an increase in tumoral CD80 + M1 macrophages in cohort B2, while cohorts A1 and C2 showed a decrease.
  • FIG.3 shows microbiome profiling of stool samples of all three cohorts, showing cohort A1 had increased bacteroidia and decreased clostridia, while cohort B2 showed the opposite.
  • FIG.4 is a pie chart showing KRAS mutation subtype frequencies in study cohorts.
  • FIG.5A is a graph showing overall survival (OS) of various KRAS mutation subtypes.
  • FIG.5B is a graph showing progression free survival (PFS) of various KRAS mutation subtypes.
  • FIG.6A is a graph showing overall survival (OS) of KRAS mutation subtype G12D on a PD-(L)1 inhibitor + chemotherapy, a CD40 agonist + chemotherapy, and a combination of a PD-(L)1 inhibitor + a CD40 agonist + chemotherapy.
  • FIG.6B is a graph showing overall survival (OS) of KRAS mutation subtype G12V on a PD-(L)1 inhibitor + chemotherapy, a CD40 agonist + chemotherapy, and a combination of a PD-(L)1 inhibitor + a CD40 agonist + chemotherapy.
  • FIG.7A is a graph showing overall survival (OS) of KRAS mutation subtypes G12D, G12R, G12V, Q61H, and no KRAS mutation on a combination of a PD-(L)1 inhibitor and chemotherapy.
  • FIG.7B is a graph showing overall survival (OS) of KRAS mutation subtypes G12D, G12R, G12V, Q61R, and no KRAS mutation on a combination of a CD40 agonist and chemotherapy.
  • FIG.7C is a graph showing overall survival (OS) of KRAS mutation subtypes G12D, G12R, G12V, Q61H, and no KRAS mutation on a combination of a PD-(L)1 inhibitor, a CD40 agonist, and chemotherapy.
  • FIG.8A is a graph showing overall survival (OS) of KRAS mutation subtypes G12D and G12V on a combination of a PD-(L)1 inhibitor and chemotherapy.
  • FIG.8B is a graph showing overall survival (OS) of KRAS mutation subtypes G12D and G12V on a combination of a CD40 agonist and chemotherapy with or without a PD-(L)1 inhibitor.
  • FIG.9 is a graph showing a correlation between SNX19 expression and KRAS mutation subtypes.
  • FIG.10A is a graph showing overall survival (OS) of all KRAS mutation subtype cohorts is associated with SNX19 expression regardless of the types of treatment received.
  • FIG.10B is a graph showing overall survival (OS) of cohort receiving a combination of an anti-PD-1 therapy and chemotherapy is associated with SNX19 expression.
  • FIG.10C is a graph showing overall survival (OS) of cohort receiving a combination of a CD40 agonist and chemotherapy is associated with SNX19 expression.
  • OS overall survival
  • FIG.10C is a graph showing overall survival (OS) of cohort receiving a combination of a CD40 agonist and chemotherapy is associated with SNX19 expression.
  • DETAILED DESCRIPTION [0035] The following descriptions and examples illustrate embodiments of the present disclosure in detail. Although the present disclosure has been described in some details by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims. [0036] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [0037] Although various features of the disclosure can be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.
  • treatment or any grammatical variant thereof of a cancer as used herein means to administer a combination therapy of a CD40 agonist, such as an anti-CD40 antibody (e.g., sotigalimab) and one or more chemotherapy drugs to a subject having the cancer, or diagnosed with the cancer, to achieve at least one positive therapeutic effect, 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.
  • a CD40 agonist such as an anti-CD40 antibody (e.g., sotigalimab)
  • chemotherapy drugs e.g., sotigalimab
  • a positive therapeutic effect 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: 1S-10S
  • the treatment regimen for the disclosed combination that is effective to treat a cancer patient can 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.
  • the treatment methods, medicaments, and disclosed uses may not be effective in achieving a positive therapeutic effect in every subject, they should do so in a statistically significant number of subjects as determined by any statistical test known in the art.
  • the term “agonist” refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the protein, such as, for example, CD40.
  • the term “mimetic”, “peptide mimetic”, or “peptidomimetic” refers to a molecule, such as a peptide, a modified peptide, or any other molecule that biologically mimics active ligands of a biomolecule, such as CD40, but have a structure that is different from the general chemical structure of the biomolecule.
  • the term “antibody” includes intact antibodies and binding fragments thereof that specifically bind to a single antigen or that specifically bind to multiple antigens (e.g., multispecific antibodies such as a bispecific antibody, a trispecific antibody, etc.). Thus, any reference to an antibody should be understood to refer to the antibody in intact form or a binding fragment unless the context requires otherwise.
  • binding fragment which can be used interchangeably with “antigen-binding fragment,” refers herein to an antibody fragment formed from a portion of an antibody comprising one or more CDRs, or any other antibody fragment that specifically binds to an antigen but does not comprise an intact native antibody structure.
  • antigen-binding fragment examples include, without limitation, a diabody, a Fab, a Fab’, a F(ab’)2, a F(ab)c, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv) 2 , a bispecific dsFv (dsFv-dsFv’), a disulfide stabilized diabody (ds diabody), a triabody, a tetrabody, a single-chain antibody molecule (scFv), an scFv dimer, a multispecific antibody, a camelized single domain antibody, a nanobody, a minibody, a domain antibody, a bivalent domain antibody, a IgNAR, a V-NAR, and a hcIgG.
  • Binding fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.
  • Fab with regard to an antibody refers to that portion of the antibody consisting of a single light chain (both variable and constant regions) bound to the variable region and first constant region of a single heavy chain by a disulfide bond.
  • Fab refers to a Fab fragment that includes a portion of the hinge region.
  • F(ab’) 2 refers to a dimer of Fab’.
  • Fc with regard to an antibody refers to that portion of the antibody consisting of the second and third constant regions of a first heavy chain bound to the second and third constant regions of a second heavy chain via disulfide bonding.
  • the Fc portion of the antibody is responsible for various effector functions such as ADCC, and CDC, but does not function in antigen binding.
  • Fv with regard to an antibody refers to the smallest fragment of the antibody to bear the complete antigen binding site. An Fv fragment consists of the variable region of a single light chain bound to the variable region of a single heavy chain.
  • Single-chain Fv antibody or “scFv” refers to an engineered antibody consisting of a light chain variable region and a heavy chain variable region connected to one another directly or via a peptide linker sequence (Huston J. S. et al., Proc Natl Acad Sci USA, 85:5879(1988)).
  • Single-chain Fv-Fc antibody or “scFv-Fc” refers to an engineered antibody consisting of a scFv connected to the Fc region of an antibody.
  • “Camelized single domain antibody,” “heavy chain antibody,” or “HCAb” refers to an antibody that contains two VH domains and no light chains (Riechmann L.
  • Heavy chain antibodies were originally derived from Camelidae (camels, dromedaries, and llamas). Although devoid of light chains, camelized antibodies have an authentic antigen-binding repertoire (Hamers-Casterman C. et al., Nature. June 3; 363(6428):446-8 (1993); Nguyen V. K. et al.
  • VHH domain The variable domain of a heavy chain antibody (VHH domain) represents the smallest known antigen-binding unit generated by adaptive immune responses (Koch-Nolte F. et al., FASEB J. November; 21(13):3490-8. Epub 2007 Jun.15 (2007)).
  • Nemobody refers to an antibody fragment that consists of a VHH domain from a heavy chain antibody and two constant domains, CH2 and CH3.
  • “Diabody” refers to a small antibody fragment with two antigen-binding sites, wherein the fragments comprise a VH domain connected to a VL domain in the same polypeptide chain (VH-VL or VL-VH) (see, e.g., Holliger P. et al., Proc Natl Acad Sci USA. July 15; 90(14):6444-8 (1993); EP404097; WO93/11161).
  • VH-VL or VL-VH polypeptide chain
  • Domain antibody refers to an antibody fragment containing only the variable region of a heavy chain or the variable region of a light chain.
  • two or more VH domains are covalently joined with a peptide linker to create a bivalent or multivalent domain antibody.
  • the two V H domains of a bivalent domain antibody can target the same or different antigens.
  • a “(dsFv)2” comprises three peptide chains: two VH moieties linked by a peptide linker and bound by disulfide bridges to two V L moieties.
  • a “bispecific ds diabody” comprises VH1-VL2 (linked by a peptide linker) bound to VL1-VH2 (also linked by a peptide linker) via a disulfide bridge between V H1 and V L1 .
  • a “bispecific dsFv” or dsFv-dsFv′” comprises three peptide chains: a VH1-VH2 moiety wherein the heavy chains are linked by a peptide linker (e.g., a long flexible linker) and bound to VL1 and VL2 moieties, respectively, via disulfide bridges, wherein each disulfide paired heavy and light chain has a different antigen specificity.
  • a peptide linker e.g., a long flexible linker
  • an “scFv dimer” is a bivalent diabody or bivalent ScFv (BsFv) comprising VH-VL (linked by a peptide linker) dimerized with another VH-VL moiety such that V H 's of one moiety coordinate with the V L ’s of the other moiety and form two binding sites which can target the same antigens (or epitopes) or different antigens (or epitopes).
  • an “scFv dimer” is a bispecific diabody comprising VH1-VL2 (linked by a peptide linker) associated with V L1 -V H2 (also linked by a peptide linker) such that V H1 and V L1 coordinate and V H2 and V L2 coordinate and each coordinated pair has a different antigen specificity.
  • biological sample or “sample” refers to any solid or liquid sample isolated from an individual or a subject.
  • tissue sample e.g., tissue sample
  • liquid sample e.g., blood
  • a biopsy material e.g., solid tissue sample
  • blood e.g., whole blood
  • sample can be, for example, fresh, fixed (e.g., formalin-, alcohol- or acetone-fixed), paraffin-embedded or frozen prior to an analysis.
  • the biological sample is obtained from a tumor (e.g., a pancreatic cancer).
  • a “test biological sample” is the biological sample that has been the subject of analysis, monitoring, or observation.
  • an “individual” or a “subject” includes animals, such as human (e.g., human individuals) and non-human animals.
  • an “individual” or “subject” is a patient under the care of a physician.
  • the subject can be a human patient or an individual who has, is at risk of having, or is suspected of having a disease of interest (e.g., cancer) and/or one or more symptoms of the disease.
  • the subject can also be an individual who is diagnosed with a risk of the condition of interest at the time of diagnosis or later.
  • non-human animals includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, non- human primates, and other mammals, such as e.g., sheep, dogs, cows, chickens, and non- mammals, such as amphibians, reptiles, etc.
  • mammals e.g., rodents, e.g., mice, non- human primates, and other mammals, such as e.g., sheep, dogs, cows, chickens, and non- mammals, such as amphibians, reptiles, etc.
  • CD40 Cluster of differentiation 40
  • APCs antigen presenting cells
  • CD40L CD40 ligand
  • CD40-CD40L complex The formation of the CD40-CD40L complex on resting cells induces proliferation, immunoglobulin class switching, antibody secretion, and also plays a role in the development of germinal centers and the survival of memory B cells, which are all important for the humoral immune response.
  • the binding of CD40L to CD40 on dendritic cells (DC) induces DC maturation, as evidenced by an increase in the expression of co-stimulating molecules, such as the B7 family of molecules (CD80, CD86), and an increase in the production of pro- inflammatory cytokines, such as interleukin 12. This leads to strong T-cell response.
  • CD40 is overexpressed in a wide range of malignant cells.
  • CD40 The role of CD40 in inhibiting tumors and stimulating the immune system makes CD40 an attractive target for antibody-based immunotherapy.
  • Anti-CD40 antibodies can act against tumor cells through several mechanisms: (i) the effector function of antibodies, such as ADCC; (ii) the direct cytotoxic effect on tumor cells; and (iii) the activation of the antitumor immune response.
  • Generating productive downstream signals from TNF receptor superfamily is dependent on agonistic compounds having a very precise structure and three- dimensional organization.
  • Exemplary agonistic compounds include, without limitation, a CD40 antibody or antigen binding fragment thereof, a CD40L fragment, a CD40 ligand fusion protein, and a CD40L mimetic.
  • the CD40 antibody or antigen binding fragment thereof includes, without limitation, sotigalimab, selicrelumab, ChiLob7/4. mitazalimab (ADC- 1013), SEA-CD40, CP-870,893, dacetuzumab, SGN-40, CDX-1140, giloralimab (ABBV-927), and APX005M.
  • the CD40 ligand fusion protein is HERA-CD40L or MEDI5083.
  • the CD40 agonist can be combined with other therapeutic options, such as other immunomodulators or checkpoint inhibitors (e.g., a PD-(L)1 agonist such as an anti-PD-(L)1 antibody or antigen binding fragment thereof).
  • other therapeutic options can include, but not limited to, one or more of chemotherapy, a kinase inhibitor, a vaccine, radiotherapy, surgery, stem cell therapy, gene therapy, and other biologics.
  • KRAS Mutation Subtypes [0076] The KRAS gene, located at chromosome 12p12.1, is a member of the RAS gene family and encodes the KRAS protein (21 kDa).
  • KRAS normally operates as a molecular switch, activating downstream pathways when GTP-bound, but inactive when GDP-bound following the hydrolysis of the ⁇ -phosphate. This reaction is catalyzed by GTPase-activating proteins (GAPs), while the exchange of the GDP for a new GTP is facilitated by guanine nucleotide exchange factors (GEFs).
  • GAPs GTPase-activating proteins
  • GEFs guanine nucleotide exchange factors
  • the activating alleles found in KRAS vary substantially across cancers, indicating possible differences in signaling behavior of the mutant proteins that exploit the environment of the specific cellular context.
  • KRAS protein When mutated at one of its four hotspot codons – 12, 13, 61, or 146 – KRAS protein hyperactivates many downstream effector pathways, such as the MAPK and PI3K-AKT signaling pathways.
  • Activating KRAS mutations result in elevated engagement of downstream pathways by increasing the steady-state levels of GTP-bound KRAS.
  • mutations to codons 12, 13, and 61 reduce the rate of intrinsic and/or GAP-mediated hydrolysis, and mutations at 13 and 61, but not 12, also enhance the rate of nucleotide exchange.
  • KRAS mutation is known to be the initiating genetic event for PDAC.
  • KRAS G12D mutation alone results in pancreatic intraepithelial neoplasm formation and infrequent protracted onset of PDAC.
  • KRAS mutation subtypes in the order of frequency in PDAC were: G12D, G12V, G12R, Q61H, Q61L and G12C. The KRAS G12 mutation accounts for 99% of all mutations.
  • KRAS mutant specificity also plays an important role in pancreatic cancer prognosis.
  • KRAS mutations are associated with more aggressive cancers and a shorter survival time (Bournet et al., Clin Transl Gastroenterol. 2016 Mar 24; 7:e157).
  • KRAS Q61 mutations were associated with improved survival compared with KRAS G12 mutant patients (Witkiewicz et al., Nat Commun. 2015 Apr 9; 6:6744).
  • KRAS mutations affect the prognosis of PDAC patients.
  • the cancer treatment include a CD40 agonist (e.g., sotigalimab).
  • the CD40 agonist e.g., sotigalimab
  • additional therapies such as, but not limited to an immunomodulator or checkpoint inhibitor (e.g., a PD-(L)1 inhibitor), chemotherapy (e.g., gemcitabine and nab- paclitaxel), a kinase inhibitor, a vaccine, radiotherapy, surgery, stem cell therapy, gene therapy, and other biologics.
  • a method of aiding a treatment of a subject with cancer comprising: (a) determining a KRAS mutation subtype of a biological sample obtained from the subject; and (b) aiding the treatment of the subject with a combination a CD40 agonist and chemotherapy, wherein the KRAS mutation subtype is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • a method for treating a subject with cancer comprising: (a) determining a KRAS mutation subtype of a biological sample obtained from the subject; and (b) treating the subject with a combination of a CD40 agonist and chemotherapy, wherein the KRAS mutation subtype is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • the amino acid N is selected from the group consisting of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamine (Q), glutamic acid (E), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), and valine (V).
  • the amino acid N is aspartic acid (D).
  • CD40 agonist refers to an agent that specifically binds to CD40 to activate CD40, similar to the binding of CD40 ligand.
  • a CD40 agonist can include a compound that binds to CD40 for receptor activation.
  • a CD40 agonist can also be a compound that mimics the CD40 ligand that binds and activates CD40.
  • the CD40 agonist can be an antibody, e.g. a monoclonal antibody or antigen-binding fragment thereof to CD40.
  • the CD40 agonist can be a CD40L fragment, a CD40 ligand fusion protein (e.g., HERA-CD40L or MDI5083), and a CD40L mimetic.
  • a specific biologic name is referring to herein, it also can include its biosimilar as well as the reference product biologic.
  • a biological sample e.g., a bulk tumor tissue and/or blood
  • a bulk tissue sample or blood sample can be subjected whole exome and transcriptome analysis using any of known techniques in the art (e.g., the ImmunoID NeXT platform, Personalis, Inc.).
  • Various computational methods to identify specific allelic variants from whole exome and transcriptome data are well known in the art.
  • variants can be identified by comparing tumor and normal sequencing and/or comparing to a reference genome. Due to the high frequency of KRAS mutations in pancreatic ductal adenocarcinoma (PDAC), a computational method specifically tailored to sensitively detect KRAS allelic variants can be used.
  • KRAS variant calling method can be used to compare tumor sequencing data not to a normal tissue but to a reference genome, thus including germline as well as somatic mutations.
  • the biological samples can be obtained from a subject, e.g., a subject having, suspected of having, or at risk of developing cancer selected from, but not limited to, a pancreatic cancer, an endometrial cancer, a non-small cell lung cancer (NSCLC), a renal cell carcinoma ((RCC), e.g. clear cell RCC, non-clear cell RCC), a urothelial cancer, a head and neck cancer (e.g.
  • a subject having, suspected of having, or at risk of developing cancer selected from, but not limited to, a pancreatic cancer, an endometrial cancer, a non-small cell lung cancer (NSCLC), a renal cell carcinoma ((RCC), e.g. clear cell RCC, non-clear cell RCC), a urothelial cancer, a head and neck cancer (e.g.
  • a melanoma e.g., advanced melanoma such as Stage III-IV high-risk melanoma, unresectable or metastatic melanoma
  • a bladder cancer e.g., a hepatocellular carcinoma, a breast cancer (e.g., triple negative breast cancer, ER + /HER2 ⁇ breast cancer), an ovarian cancer, a gastric cancer (e.g.
  • metastatic gastric cancer or gastroesophageal junction adenocarcinoma a colorectal cancer, a glioblastoma, a biliary tract cancer, a glioma (e.g., recurrent malignant glioma with a hypermutator phenotype), Merkel cell carcinoma (e.g., advanced or metastatic Merkel cell cancer), Hodgkin lymphoma, non-Hodgkin lymphoma (e.g.
  • PMBCL primary mediastinal B-cell lymphoma
  • a cervical cancer an advanced or refractory solid tumor
  • a small cell lung cancer e.g., stage IV non-small cell lung cancer
  • a non-squamous non-small cell lung cancer desmoplastic melanoma
  • a pediatric advanced solid tumor or lymphoma a mesothelin-positive pleural mesothelioma
  • an esophageal cancer an anal cancer
  • a salivary cancer a prostate cancer
  • a carcinoid tumor a primitive neuroectodermal tumor (pNET), and a thyroid cancer.
  • the cancer is a pancreatic cancer.
  • the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • the methods provided herein can enable identifying a cancer patient with a specific KRAS mutation subtype who will benefit from a combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy.
  • a subject who is likely to respond to the combination therapy can be administered e.g., sotigalimab, at least one chemotherapy drug (e.g., gemcitabine and nab-paclitaxel), and optionally a PD-(L)1 inhibitor.
  • the KRAS mutation subtype for a CD40 agonist is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • the amino acid N is selected from the group consisting of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamine (Q), glutamic acid (E), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), and valine (V).
  • the amino acid N is aspartic acid (D).
  • an CD40 agonist e.g., anti-CD40 antibody such as sotigalimab
  • chemotherapy e.g., gemcitabine, nab-paclitaxel
  • a CD40 agonist e.g., a CD40 antibody such as sotigalimab
  • a CD40 agonist is an anti-CD40 antibody.
  • the anti-CD40 antibody is selected from the group consisting of sotigalimab (APX005M), selicrelumab, ChiLob7/4. mitazalimab (ADC-1013), SEA-CD40, CP-870,893, dacetuzumab, SGN-40, CDX-1140, and giloralimab (ABBV-927).
  • the anti-CD40 antibody is sotigalimab.
  • the method can include administering 240 mg of sotigalimab to the patient about every two weeks. In some embodiments, the method can include administering 240 mg of sotigalimab to the patient about every four weeks.
  • one or more chemotherapy drugs can be selected from the group consisting of gemcitabine, nab-paclitaxel, folfirinox, nitrogen mustard / oxazaphosphorine, nitrosourea, triazene, and alkyl sulfonates, anthracycline antibiotics such as doxorubicin and daunorubicin, taxanes such as Taxol brand and docetaxel, vinca alkaloids such as vincristine and vinblastine, 5-fluorouracil (5-FU), leucovorin, Irinotecan, idarubicin, mitomycin C, oxaliplatin, raltitrexed, pemetrexed, tamoxifen, cisplatin, carboplatin, methotrexate, a Tinomycin D, mitoxantrone, brenoxane, mitramycin, methotrexate, paclitaxel, 2-methoxyestradiol
  • the one or more chemotherapy drugs can be a combination of gemcitabine and nab-paclitaxel.
  • a chemotherapy agonist e.g., anti-CD40 antibody such as sotigalimab
  • a medical practitioner e.g., a doctor
  • administering an anti- CD40 antibody e.g., sotigalimab, selicrelumab, ChiLob7/4.
  • any therapy described herein e.g., a combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy or a therapy other than the combination therapy
  • a combination therapy including a CD40 agonist e.g., anti-CD40 antibody such as sotigalimab
  • chemotherapy or a therapy other than the combination therapy can include one or more additional therapeutic agents.
  • the additional therapeutic agents is an anti-PD-(L)-1 inhibitor (e.g., nivolumab).
  • any therapy described herein can be co-administered (administered in combination) with one or more additional anti-tumor agents.
  • any therapy described herein can include one or more agents for treating, for example, pain, nausea, and/or one or more side-effects of the combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy.
  • the combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy can be, e.g., simultaneous or successive.
  • one or more chemotherapy drugs and an anti-CD40 antibody can be administered at the same time or one or more chemotherapy drugs can be administered first in time and an anti-CD40 antibody administered second in time, or vice versa.
  • the dosing frequency of the one or more chemotherapy drugs and the anti-CD40 antibody can be different or same. In one embodiment, the dosing frequency is different.
  • An exemplary dosing frequency of the combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy can be once in a few weeks, for example, 1 week, 2 weeks, 3 weeks, 4 weeks or 1 month, or 6 weeks. IV.
  • Sorting nexin 19 promotes dopamine D1R receptor recycling, with knockdown yielding reduced cAMP signaling.
  • D1R is also associated with histamine H4 receptor signaling (Amatya et al., J Mol Sci.2021 Feb 26;22(5):2319).
  • N-arylpiperazine-containing compound C2 enhances sunitinib efficacy in SW1990 (PDAC) xenograft model by reducing growth, reversed by a D1R specific blockade (Su et al.
  • a test biological sample e.g., a bulk tumor tissue and/or blood
  • one or more reference biological samples can be obtained from a test subject having a particular type of cancer and one or more reference subjects having the same type of cancer as the test subject both prior to and after administration of the combination therapy.
  • a bulk tissue sample can be subjected to whole exome and transcriptome analysis using any of known techniques in the art (e.g., the ImmunoID NeXT platform, Personalis, Inc.). The resulting data can be used for gene expression quantification.
  • Whole transcriptome sequencing results can be aligned using e.g., STAR, and normalized expression value in transcripts per million (TPM) can be calculated using e.g., Personalis’ ImmunoID NeXT tool, Expressionist.
  • TPM transcripts per million
  • a SNX19 expression score can be calculated by averaging the log normalized expression value for SNX19 gene.
  • the subjects can be based on the value of this SNX19 expression score, where “high” vs “low” can be defined by the median signature value across all subjects including the test subject and the one or more reference subjects.
  • a method for treating a subject with cancer comprising: (a) determining sorting nexin 19 (SNX19) expression level of a test biological sample and one or more reference biological samples, wherein a reference biological sample of the one or more reference biological samples is collected from each individual among a cohort of subjects having the same cancer, wherein the subject is part of the cohort; (b) calculating a SNX19 expression score of the subject; (c) treating the subject with a combination of a CD40 agonist and chemotherapy, wherein the SNX expression score of the subject is high as compared to a median SNX19 expression score of the cohort.
  • the method optionally comprises determining a KRAS mutation subtype of the subject.
  • the KRAS mutation subtype is a G12N, wherein glycine (G) at position 12 is substituted with an amino acid N.
  • the amino acid N is selected from the group consisting of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamine (Q), glutamic acid (E), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), and valine (V).
  • the amino acid N is aspartic acid (D).
  • the present disclosure demonstrates that the SNX19 expression score is associated with KRAS mutation subtype (FIG.9).
  • the amino acid N is aspartic acid (D)
  • the SNX19 expression score is high, which is an indicative that the patient will benefit from a CD40 agonist treatment (FIG.9; FIG.10C).
  • the amino acid N is valine (V)
  • the SNX19 expression score is low, which is an indicative that the patient will benefit from an anti-PD-(L)1 treatment, but not from a CD40 agonist treatment (FIG.9; FIG.10B).
  • the subject can then be administered an effective amount of one or more chemotherapy drugs (e.g., gemcitabine, nab-paclitaxel) and a CD40 agonist (e.g., a CD40 antibody such as sotigalimab).
  • chemotherapy drugs e.g., gemcitabine, nab-paclitaxel
  • CD40 agonist e.g., a CD40 antibody such as sotigalimab.
  • An effective amount of each chemotherapy drug and the CD40 agonist can suitably be determined by a health care practitioner taking into account, for example, the characteristics of the patient (e.g., age, sex, weight, race, etc.), the progression of the disease, and prior exposure to the drug.
  • a CD40 agonist is an anti-CD40 antibody.
  • the anti-CD40 antibody is selected from the group consisting of sotigalimab, selicrelumab, ChiLob7/4. mitazalimab (ADC-1013), SEA-CD40, CP-870,893, dacetuzumab, SGN-40, CDX-1140, giloralimab (ABBV-927), and APX005M.
  • the anti- CD40 antibody is sotigalimab.
  • the method can include administering 240 mg of sotigalimab to the patient about every two weeks.
  • one or more chemotherapy drugs can be selected from the group consisting of gemcitabine, nab-paclitaxel, folfirinox, nitrogen mustard / oxazaphosphorine, nitrosourea, triazene, and alkyl sulfonates, anthracycline antibiotics such as doxorubicin and daunorubicin, taxanes such as Taxol brand and docetaxel, vinca alkaloids such as vincristine and vinblastine, 5-fluorouracil (5-FU), leucovorin, Irinotecan, idarubicin, mitomycin C, oxaliplatin, raltitrexed, pemetrexed, tamoxifen, cisplatin, carboplatin, methotrexate, a Tinomycin D, mitoxantrone, brenoxane, mitramycin, methotrexate, paclitaxel, 2-methoxyestradiol
  • the one or more chemotherapy drugs can be a combination of gemcitabine and nab-paclitaxel.
  • a chemotherapy agonist e.g., anti-CD40 antibody such as sotigalimab
  • a medical practitioner e.g., a doctor
  • administering an anti- CD40 antibody e.g., sotigalimab, selicrelumab, ChiLob7/4.
  • any therapy described herein e.g., a combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy or a therapy other than the combination therapy
  • a combination therapy including a CD40 agonist e.g., anti-CD40 antibody such as sotigalimab
  • chemotherapy or a therapy other than the combination therapy can include one or more additional therapeutic agents.
  • the additional therapeutic agents is an anti-PD-(L)-1 inhibitor (e.g., nivolumab).
  • any therapy described herein can be co-administered (administered in combination) with one or more additional anti-tumor agents.
  • any therapy described herein can include one or more agents for treating, for example, pain, nausea, and/or one or more side-effects of the combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy.
  • the combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy can be, e.g., simultaneous or successive.
  • one or more chemotherapy drugs and an anti-CD40 antibody can be administered at the same time or one or more chemotherapy drugs can be administered first in time and an anti-CD40 antibody administered second in time, or vice versa.
  • the dosing frequency of the one or more chemotherapy drugs and the anti-CD40 antibody can be different or same. In one embodiment, the dosing frequency is different.
  • An exemplary dosing frequency of the combination therapy including a CD40 agonist (e.g., anti-CD40 antibody such as sotigalimab) and chemotherapy can be once in a few weeks, for example, 1 week, 2 weeks, 3 weeks, 4 weeks or 1 month, or 6 weeks.
  • the CD40 antibodies e.g., sotigalimab
  • an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and/or ameliorates at least one sign or symptom of a disorder (e.g., PDAC).
  • a subject is already suffering from a disorder, the regime can be referred to as a therapeutically effective regime.
  • the regime can be referred to as a prophylactically effective regime.
  • therapeutic or prophylactic efficacy can be observed in an individual subject relative to historical controls or past experience in the same subject.
  • any of the methods described herein include the administration of a therapeutically effective amount of one or more of the anti-CD40 antibodies described herein to subjects in need thereof.
  • a “therapeutically effective amount” or “therapeutically effective dosage” of an anticancer therapy is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include but are not limited to clinical results such as decreasing one or more symptoms resulting from cancer, increasing the quality of life of subjects suffering from cancer, decreasing the dose of other medications required to treat the cancer, enhancing the effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of an anti-cancer therapy is an amount sufficient to accomplish therapeutic or prophylactic treatment either directly or indirectly.
  • a therapeutically effective dosage of an anti-cancer therapy may or may not be achieved in conjunction with another anti-cancer therapy.
  • Exemplary dosages for any of the antibodies described herein are about 0.1-20 mg/kg or 0.5-5 mg/kg body weight (e.g., about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, or 20 mg/kg) or 10-1600 mg (such as any of less than 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1
  • the antibody described herein in given in an amount of about 300 to 1500 mg every three weeks. In another embodiment, the antibody described herein is given in an amount of about 300 to 1800 mg every four weeks.
  • the dosage depends on the condition of the subject and response to prior treatment, if any, whether the treatment is prophylactic or therapeutic and whether the disorder is acute or chronic, among other factors.
  • Administration can be parenteral, intravenous, oral, subcutaneous, intra-arterial, intracranial, intrathecal, intraperitoneal, intratumoral, topical, intranasal or intramuscular. In some embodiments, administration into the systemic circulation is by intravenous or subcutaneous administration. Intravenous administration can be, for example, by infusion over a period such as 30-90 min.
  • the frequency of administration depends on the half-life of the antibody in the circulation, the condition of the subject and the route of administration among other factors.
  • the frequency can be daily, weekly, monthly, quarterly, or at irregular intervals in response to changes in the subject’s condition or progression of the disorder being treated.
  • the frequency can be in two-week cycles.
  • the frequency can be in three-week cycles.
  • the frequency is four-week cycles.
  • the frequency is six-week cycles.
  • An exemplary frequency for intravenous administration is between weekly and quarterly over a continuous cause of treatment, although more or less frequent dosing is also possible.
  • an exemplary dosing frequency is daily to monthly, although more or less frequent dosing is also possible.
  • Treatment including an anti-CD40 antibody can alleviate a disease by increasing the median progression-free survival or overall survival time of subjects with cancer by at least about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or even 100%, compared to control subjects, or increase either of
  • treatment including the anti- CD40 antibody can increase the complete response rate, partial response rate, or objective response rate (complete + partial) of subjects by at least about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or even 100% compared to the control subjects.
  • control subjects receive the same treatment as subjects receiving the anti-CD40 antibody except for the anti-CD40 antibody.
  • control subjects can receive placebo alone or a combination of placebo and some chemotherapeutic agent other than the anti-CD40 antibody if such is also received by the subjects receiving the anti-CD40 antibody.
  • the anti-CD40 antibodies disclosed herein can enhance the number of activated effector memory T cells (Ki67 + CD8 + ) relative to the amount of effector memory T cells (Ki67 + CD8 + ) in the absence of one of the anti-CD40 antibodies disclosed herein.
  • the anti-CD40 antibodies disclosed herein can also enhance the number of activated myeloid dendritic cells (CD86 + ) relative to the amount of activated myeloid dendritic cells (CD86 + ) in the absence of one of the anti-CD40 antibodies disclosed herein.
  • the anti-CD40 antibodies disclosed herein can further increase the amount of tumoral CD80 + M1 macrophages.
  • the anti-CD40 antibodies can also decrease bacteroidia and increase clostridia as well as gammaproteobacteria in stool samples of subjects as compared to control subjects.
  • compositions for parenteral administration can be sterile and substantially isotonic and manufactured under GMP conditions.
  • compositions can be provided in unit dosage form (i.e., the dosage for a single administration).
  • Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries. The formulation depends on the route of administration chosen.
  • antibodies can be formulated in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline or acetate buffer (to reduce discomfort at the site of injection).
  • the solution can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • antibodies can be in lyophilized form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the concentration of antibody in liquid formulations can vary from e.g., about 10-150 mg/ml. In some formulations the concentration is about 20-80 mg/ml.
  • the additional active therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptibodies, peptides, DNA, RNA or fragments of such macromolecules; or cellular or gene therapies.
  • the combination therapy can target different, but complementary, mechanisms of action and thereby have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.
  • the combination therapy can allow for a dose reduction of one or more of the agents, thereby ameliorating, reducing or eliminating adverse effects associated with one or more of the agents.
  • the active therapeutic agents in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times.
  • the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and/or resumed during a patient’s course of therapy.
  • the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.
  • any of the CD40 agonists disclosed herein are administered or applied sequentially to one or more of the additional active therapeutic agents, e.g., where one or more of the additional active therapeutic agents is administered prior to or after the administration of the CD40 agonist according to this disclosure.
  • the antibodies are administered simultaneously with one or more of the additional active therapeutic agents, e.g., where the anti-CD40 antibody is administered at or about the same time as one or more of the additional therapeutic agents; the anti-CD40 antibody and one or more of the additional therapeutic agents can be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation).
  • the additional agent(s) are administered sequentially or simultaneously with the anti-CD40 antibody, they are considered to be administered in combination for purposes of the present disclosure.
  • the antibodies of the present disclosure can be used in combination with at least one other (active) agent in any manner appropriate under the circumstances.
  • treatment with the at least one active agent and at least one CD40 agonist of the present disclosure is maintained over a period of time.
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a CD40 agonist of the present disclosure is maintained at a constant dosing regimen.
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a CD40 agonist of the present disclosure is reduced (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), and treatment with the a CD40 agonist of the present disclosure is increased (e.g., higher dose, more frequent dosing or longer treatment regimen).
  • treatment with the at least one active agent is maintained and treatment with the a CD40 agonist of the present disclosure is reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • treatment with the at least one active agent and treatment with the a CD40 agonist of the present disclosure are reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • Treatment with antibodies of the present disclosure can be combined with other treatments effective against the disorder being treated.
  • the antibodies of the present disclosure can be combined with chemotherapy, radiation (e.g., localized radiation therapy or total body radiation therapy), stem cell treatment, surgery, other biologics.
  • Antibodies of the present disclosure can be administered with vaccines eliciting an immune response against a cancer. Such immune response is enhanced by the antibody of the present disclosure.
  • the vaccine can include an antigen expressed on the surface of the cancerous cell and/or tumor of a fragment thereof effective to induce an immune response, optionally linked to a carrier molecule.
  • one or more of the additional therapeutic agents is an immunomodulatory agent.
  • Suitable immunomodulatory agents include CD40L, B7, and B7RP1; activating monoclonal antibodies (mAbs) to stimulatory receptors, such as, anti-CD38, anti-ICOS, and 4-IBB ligand; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines such as dendritic cell cancer vaccines; cytokines/chemokines, such as, IL1, IL2, IL12, IL18, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN ⁇ / ⁇ , M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharides (LPS); indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immune- stimulatory oligonucleotides.
  • mAbs monoclonal antibodies
  • one or more of the additional therapeutic agents is a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, gemcitabine, nab-paclitaxel, folfirionx, nitrogen mustard / oxazaphosphorine, nitrosourea, triazene, and alkyl sulfonates, anthracycline antibiotics such as doxorubicin and daunorubicin, taxanes such as Taxol brand and docetaxel, vinca alkaloids such as vincristine and vinblastine, 5- fluorouracil (5-FU), leucovorin, Irinotecan, idarubicin, mitomycin C, oxaliplatin, raltitrexed, pemetrexed, tamoxifen, cisplatin, carboplatin, methotrexate, a Tinomycin D, mitoxantrone, brenoxane, mitra
  • Chemotherapeutic agents can also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • anti-estrogens including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and torem
  • combination therapy includes a chemotherapy regimen that includes one or more chemotherapeutic agents.
  • combination therapy includes administration of a hormone or related hormonal agent.
  • Additional treatment modalities that can be used in combination with a CD40 agonist include radiotherapy, an antibody against a tumor antigen, a complex of an antibody and toxin, a T cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy), including TLR agonists which are used to stimulate such antigen presenting cells.
  • the present disclosure contemplates the use of the CD40 agonist described herein in combination with RNA interference-based therapies to silence gene expression.
  • RNAi begins with the cleavage of longer double-stranded RNAs into small interfering RNAs (siRNAs).
  • siRNAs small interfering RNAs
  • One strand of the siRNA is incorporated into a ribonucleoprotein complex known as the RNA-induced silencing complex (RISC), which is then used to identify mRNA molecules that are at least partially complementary to the incorporated siRNA strand.
  • RISC can bind to or cleave the mRNA, both of which inhibits translation.
  • the present disclosure contemplates the use of the CD40 agonist described herein in combination with inhibitors of the immune-checkpoint receptors and ligands (e.g., an anti-PD- (L)1 antibody, such as nivolumab), as well as yet-to-be-described immune-checkpoint receptors and ligands.
  • inhibitors of the immune-checkpoint receptors and ligands e.g., an anti-PD- (L)1 antibody, such as nivolumab
  • an anti-PD- (L)1 antibody such as nivolumab
  • Approved anti-PD-1 antibodies include nivolumab (e.g., OPDIVO®; Bristol Myers Squibb) and pembrolizumab (e.g., KEYTRUDA®; Merck) for various cancers, including squamous cell carcinoma, classical Hodgkin lymphoma and urothelial carcinoma.
  • nivolumab e.g., OPDIVO®; Bristol Myers Squibb
  • pembrolizumab e.g., KEYTRUDA®
  • Merck e.g., KEYTRUDA®
  • cancers including squamous cell carcinoma, classical Hodgkin lymphoma and urothelial carcinoma.
  • Approved anti-PD-L1 antibodies include avelumab (e.g., BAVENCIO®; EMD Serono & Pfizer), atezolizumab (e.g., TECENTRIQ®; Roche/Genentech), and durvalumab (e.g., IMFINZI®; AstraZeneca) for certain cancers, including urothelial carcinoma.
  • avelumab e.g., BAVENCIO®; EMD Serono & Pfizer
  • atezolizumab e.g., TECENTRIQ®; Roche/Genentech
  • durvalumab e.g., IMFINZI®; AstraZeneca
  • the immune checkpoint inhibitor is selected from MEDI-0680 nivolumab, pembrolizumab, avelumab, atezolizumab, budigalimab, BI-754091, camrelizumab, cosibelimab, durvalumab, dostarlimab, cemiplimab, sintilimab, tislelizumab, toripalimab, retifanlimab, sasanlimab, and zimberelimab (AB122).
  • the immune checkpoint inhibitor is MEDI-0680 (AMP-514; WO2012/145493) or pidilizumab (CT-011).
  • Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224.
  • the present disclosure contemplates the use of a CD40 agonist according to this disclosure with a PD-(L)1 inhibitor.
  • the PD-(L)1 inhibitor is nivolumab.
  • the present disclosure contemplates combination with a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • a cytokine that inhibits T cell activation e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines
  • a cytokine that stimulates T cell activation for stimulating an immune response.
  • T cell responses can be stimulated by a combination of the disclosed a CD40 agonist and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, PVRIG, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and/or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS- L, OX40, OX40L, GITR, GITRL, CD70, CD27, DR3 and CD2.
  • an antagonist of a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • CD40 agonist of the present disclosure for the treatment of cancer
  • agents that can be combined with the CD40 agonist of the present disclosure for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • the CD40 agonist described herein can be combined with antagonists of KIR, such as lirilumab.
  • the disclosed CD40 agonist can be combined with one or more of: agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-Ll/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), or reverse/prevent T cell anergy or exhaustion), and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • agonistic agents that ligate positive costimulatory receptors e.g., blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor
  • the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody.
  • CTLA-4 antibodies include, for example, ipilimumab (e.g., YERVOY®; Bristol Myers Squibb) or tremelimumab.
  • the immuno- oncology agent is a PD-Ll antagonist, such as an antagonistic PD-Ll antibody.
  • Suitable PD-Ll antibodies include, for example, atezolizumab (MPDL3280A; WO2010/077634) (e.g., TECENTRIQ®; Roche/Genentech), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).
  • the immuno- oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.
  • Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273).
  • the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody.
  • Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433).
  • the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody.
  • Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO11/028683).
  • the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody.
  • Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.
  • the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody.
  • Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).
  • the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody.
  • Suitable CD27 antibodies include, for example, varlilumab.
  • the immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).
  • combination of a CD40 agonist according to this disclosure with an agent directed at Trop-2 e.g., the antibody drug conjugate, sacituzumab govitecan-hziy
  • an agent directed at Trop-2 e.g., the antibody drug conjugate, sacituzumab govitecan-hziy
  • combination of the CD40 agonist described herein with an agent that inhibits the CD47-SIRP ⁇ pathway is contemplated.
  • An example of an anti-CD47 antibody is magrolimab.
  • a combination is an antibody of the present disclosure with a second antibody directed at a surface antigen preferentially expressed on the cancer cells relative to control normal tissue.
  • antibodies that can be administered in combination therapy with antibodies of the present disclosure for treatment of cancer include Herceptin® (trastuzumab) against the HER2 antigen, Avastin® (bevacizumab) against VEGF, or antibodies to the EGF receptor, such as (Erbitux®, cetuximab), and Vectibix® (panitumumab).
  • agents that can be administered include antibodies or other inhibitors of any of PD-1, PD-L1, CTLA-4, 4-1BB, BTLA, PVRIG, VISTA, TIM-3 and LAG-3; or other downstream signaling inhibitors, e.g., mTOR and GSK3 ⁇ inhibitors; and cytokines, e.g., interferon- ⁇ , IL-2, and IL-15.
  • additional agents include: ipilimumab, pazopanib, sunitinib, dasatinib, pembrolizumab, INCR024360, dabrafenib, trametinib, atezolizumab (MPDL3280A), erlotinib (e.g., TARCEVA®), cobimetinib, nivolumab, and zimberelimab.
  • the choice of a second antibody or other agent for combination therapy depends on the cancer being treated.
  • the cancer is tested for expression or preferential expression of an antigen to guide selection of an appropriate antibody.
  • the isotype of the second antibody is human IgG1 to promote effector functions, such as ADCC, CDC and phagocytosis.
  • the present disclosure encompasses pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • kits containing one or more of the antibodies disclosed herein as well as one or more pharmaceutically acceptable excipients or carriers such as, without limitation, phosphate buffered saline solutions, water, sterile water, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, sesame oil, emulsions such as oil/water emulsions or water/oil emulsions, microemulsions, nanocarriers and various types of wetting agents).
  • pharmaceutically acceptable excipients or carriers such as, without limitation, phosphate buffered saline solutions, water, sterile water, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, sesame oil, emulsions such as oil/water emulsions or water/oil emulsions, microemulsions, nanocarriers and various types of wetting agents).
  • kits of the present disclosure can also be included in the kits of the present disclosure along with the carrier, diluent, or excipient.
  • a pharmaceutically acceptable carrier appropriate for use in the antibody compositions disclosed herein is sterile, pathogen free, and/or otherwise safe for administration to a subject without risk of associated infection and other undue adverse side effects.
  • the respective agents can be provided in separate vials with instructions for combination followed by administration or instructions for separate administration.
  • the kit can also include written instructions for proper handling and storage of any of the CD40 agonists disclosed herein.
  • EXAMPLES [0132] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
  • Clinical Trial Phase 2 Study [0133] Results from a Phase 1b trial evaluating gemcitabine and nab-paclitaxel with or without nivolumab demonstrated promising clinical activity in patients with untreated metastatic pancreatic ductal adenocarcinoma (mPDAC) (O’Hara et al. Lancet Oncol.2021;22(1): 118-131).
  • mPDAC metastatic pancreatic ductal adenocarcinoma
  • Phase 1b trial was a dose-ranging study to assess safety and clinical activity and to determine the recommended Phase 2 dose of sotigalimab in combination with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab.
  • gemcitabine Gam
  • NP nab-paclitaxel
  • results from the follow-on, randomized phase 2 trial NCT03214250) evaluating gemcitabine and nab-paclitaxel with or without nivolumab.
  • the first 12 participants were randomized 4:1:1 to A1 cohort (gemcitabine + nab- paclitaxel + nivolumab), B2 cohort (gemcitabine + nab-paclitaxel + sotigalimab 0.3 mg/kg), or C2 cohort (gemcitabine + nab-paclitaxel + nivolumab + sotigalimab 0.3 mg/kg).
  • the remaining participants were randomized in a 1:1:1 allocation.
  • the 12 dose-limiting toxicity (DLT)- evaluable participants from Phase 1b were included in Phase 2 efficacy analyses.
  • DLT dose-limiting toxicity
  • nivolumab 240 mg was administered.
  • Tumor biopsies were collected at screening and cycle 2 day 4 (cohorts with sotigalimab) or day 8 (cohorts without sotigalimab) and end of treatment (optional).
  • Baseline (cycle 1 day 1 or at screening) and on-treatment blood, tumor tissue, and stool samples were collected and analyzed for tumor and immune biomarkers using a variety of technologies known in the art. Planned enrollment of 35 patients/arm provided 81% power for testing the alternative of 58% OS rate vs.35%, using a 1-sided, 1-sample Z test with 5% type I error. Trial was not powered for cross-arm comparison.
  • Demographics and Baseline Characteristics of Study Participants [0139] All participants had a minimum follow-up of 15 months at the time of the data snapshot presented as Table.1 (March 2021).
  • Baseline characteristics were generally balanced across arms, inclusive of tumor burden, presence of liver metastases (25 [73.5%], 28 [75.7%], 27 [73.0%] for cohorts A1, B2, and C2, respectively) and stage at initial diagnosis (stage 1-3 versus stage 4 [stage 4: 27 (79.4%), 28 (75.5%), 27 (73.0%) for A1, B2, and C2, respectively]) (Table 1).
  • Efficacy Median time on treatment was 5.2, 5.1, and 4.7 months for cohorts A1, B2, and C2, respectively.
  • SNVs single nucleotide variants
  • KRAS variant calling method was used to compare tumor sequencing data not to a normal tissue but to a reference genome, thus including germline as well as somatic mutations. Additionally, only the A11, G12, G13, and Q61 KRAS sites were considered as these are the sites most commonly mutated in PDAC.
  • o Minor allele frequency > 1% i.e., 1% of sequence reads show the KRAS allelic variant compared to reference
  • the sorting nexin (SNX) family is composed of proteins involved in protein sorting and transport. SNX19 has been shown to have a function in intracellular vesicle trafficking and exocytosis (Harashima et al., J.

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Abstract

La présente invention concerne des procédés de traitement du cancer avec un sous-type de mutation KRAS spécifique avec une polythérapie avec un agoniste CD40 et un ou plusieurs médicaments de chimiothérapie.
PCT/US2022/034080 2021-06-17 2022-06-17 Procédés de traitement de sous-types de mutation kras avec un agoniste cd40 WO2022266496A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090075272A1 (en) * 2006-01-20 2009-03-19 Hollmann C Annette Method to Identify CD40-Sensitive Cells Using Gene Expression
US20090304687A1 (en) * 2005-12-09 2009-12-10 Seattle Genetics , Inc. Methods of using cd40 binding agents
WO2021081212A1 (fr) * 2019-10-24 2021-04-29 Amgen Inc. Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kras g12c et de kras g12d dans le traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090304687A1 (en) * 2005-12-09 2009-12-10 Seattle Genetics , Inc. Methods of using cd40 binding agents
US20090075272A1 (en) * 2006-01-20 2009-03-19 Hollmann C Annette Method to Identify CD40-Sensitive Cells Using Gene Expression
WO2021081212A1 (fr) * 2019-10-24 2021-04-29 Amgen Inc. Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kras g12c et de kras g12d dans le traitement du cancer

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