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WO2025155971A1 - Anticorps de récepteur du récepteur anti-activine 1c (alk-7) - Google Patents

Anticorps de récepteur du récepteur anti-activine 1c (alk-7)

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Publication number
WO2025155971A1
WO2025155971A1 PCT/US2025/012396 US2025012396W WO2025155971A1 WO 2025155971 A1 WO2025155971 A1 WO 2025155971A1 US 2025012396 W US2025012396 W US 2025012396W WO 2025155971 A1 WO2025155971 A1 WO 2025155971A1
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WO
WIPO (PCT)
Prior art keywords
antibody
mage
cancer
alk
gage
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Pending
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PCT/US2025/012396
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English (en)
Inventor
Teri Heiland
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Immunomic Therapeutics Inc
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Immunomic Therapeutics Inc
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Publication of WO2025155971A1 publication Critical patent/WO2025155971A1/fr
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    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the invention relates to specifically disclosed antibodies that bind to the ALK- 7 protein as well as methods and compositions for detecting, diagnosing, or prognosing a disease or disorder associated with aberrant ALK-7 expression or inappropriate function of ALK-7 protein using antibodies or fragments or variants thereof, or related molecules, that bind to ALK-7. Discussion of the Related Art [0002] In the following discussion, certain articles and methods will be described for background and introductory purposes. None contained herein is to be construed as an "admission" of prior art.
  • Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for new drugs effective in monotherapy or in combination with existing agents as first line therapy, and as second and third line therapies in treatment of resistant tumors. [0004] Recent efforts in treating cancer focus on targeted therapeutics or treatments that specifically inhibit vital signaling pathways. However, drug resistance and cancer progression invariably develop.
  • ALK-7C Activin receptor-like kinases
  • ACVR1 Activin receptor-like kinases
  • Activins have been shows to play pivotal roles as regulatory factors in conditions characterized by immune disorders, such as allergies, autoimmune diseases, and various cancers. These proteins exert their signaling function by binding to a heteromeric tetramer consisting of two type I receptors (ACVR1c, also known as ALK7, or ACVR1b/ALK4) and two type II receptors (either ACVR2a or ACVR2b).
  • ACVR1c also known as ALK7, or ACVR1b/ALK4
  • ACVR2a or ACVR2b type II receptors
  • ALK-7C has also been shown to substantially impact development. For example, in Xenopus, active ALK-7C is associated with the induction of the mesoendodermal markers.
  • ALK-7C is primarily expressed in the central nervous system, where the signaling pathway is suggested to be involved in neuronal proliferation and differentiation, as well as the pancreas and colon. Morevoer, Alk7 knockout mice have been shown to present with metabolic issues, including reduced insulin sensitivity, impaired glucose tolerance, and enlargement of pancreatic islands. [0008] Additionally, the loss of ALK-7C in cancer has been, thus far, consistently associated with poor outcomes. For example, in gallbladder cancer, expression of ALK- 7C has been associated with better survival compared to patients with ALK-7C-negative squamous cell, adenosquamous, and adenocarcinomas of the gallbladder.
  • ALK-7C expression becomes lost with increased cancer grade and stage.
  • Activin B treatment can restore the functional effects of this pathway and inhibit proliferation.
  • a more molecular examination of ALK-7C in ovarian cancer has indicated that ALK-7C signaling, via the SMAD2/3 axis, can upregulate and downregulate cyclin G2 and Skp1 and Skp2, respectively, whereby inhibiting cell cycle and acting as a tumor suppressor.
  • ALK-7C regulation in cancer may be a result of post- transcriptional regulation.
  • the bispecific antibody comprises (a) an anti- CXCL12 antibody; (b) an anti-CXCR4 antibody; (c) an anti-CD47 antibody; (d) a checkpoint inhibitor antibody, preferably an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIM-3 antibody, and/or an anti-LAG3 antibody, (e) an anti-T-cell co-receptor antibody (e.g., an anti-4-1BB (CD137) antibody or an anti-ICOS (CD278) antibody); and/or (f) an anti-neoantigen antibody.
  • a checkpoint inhibitor antibody preferably an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIM-3 antibody, and/or an anti-LAG3 antibody
  • an anti-T-cell co-receptor antibody e.g., an anti-4-1BB (CD137) antibody or an anti-ICOS (CD278) antibody
  • the neoantigen is selected from MAGE-A1, MAGE- A2, MAGE- A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, GAGE-I, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-I, RAGE- 1, LB33/MUM-1, PRAME, NAG, MAGE- Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE- C1/CT7, MAGE-C2, NY-ESO-I, LAGE-I, SSX-I, SSX-2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, SCP-I and XAGE, melanocyte differentiation antigens,
  • the antibody further comprises: (a) a detectable label, preferably wherein said detectable label is a radiolabel, an enzyme, a fluorescent label, a luminescent label, or a bioluminescent label; or (b) a conjugated therapeutic or cytotoxic agent.
  • the detectable label is selected from 125 I, 131 I, In, 90 Y, 99 Tc, 177 Lu, 166 Ho, or 153 Sm, or a biotinylated molecule.
  • the conjugated therapeutic or cytotoxic agent is selected from the group consisting of (a) an anti-metabolite; (b) an alkylating agent; (c) an antibiotic; (d) a growth factor; (e) a cytokine; (f) an anti-angiogenic agent; (g) an anti-mitotic agent; (h) an anthracycline; (i) toxin; and/or (j) an apoptotic agent.
  • kits comprising and nucleic acids encoding the anti-ALK-7 antibodies as described herein. Additionally, vectors and host cells comprising such nucleic acid molecules are also provided.
  • Uses of the anti-ALK-7 antibodies are also provided, including uses selected from (a) a method of detecting aberrant expression of the ALK-7 protein; (b) a method for diagnosing a disease or disorder associated with aberrant ALK-7 protein expression or activity; (c) a method of inhibiting ALK-7 activity; (d) a method of inhibiting ALK-7 and ACVR2 hetero-tetrameric binding; (e) a method of inhibiting SMAD2 & SMAD3 phosphorylation; (f) a method of inhibiting the formation of FoxP3+ iTREG cells; and/or (g) a method of treating, preventing or ameliorating a disease or disorder associated with aberrant ALK-7 expression or activity.
  • the use further comprises co-administering other anti-cancer therapies, such as a chemotherapeutic agent, radiation therapy, a cancer therapy, an immunotherapy, or a cancer vaccine, a cytokine, a toxin, a pro-apoptotic protein or a chemotherapeutic agent.
  • other anti-cancer therapies such as a chemotherapeutic agent, radiation therapy, a cancer therapy, an immunotherapy, or a cancer vaccine, a cytokine, a toxin, a pro-apoptotic protein or a chemotherapeutic agent.
  • Figure 3A provides the weight kinetics data and Figure 3B shows fasting blood glucose measurements for Antibody 5.
  • DETAILED DESCRIPTION [0030] The invention is directed to specific anti-ALK-7 antibodies, related compositions, and their use. DEFINITIONS [0031] The following definitions are provided for specific terms which are used in the following written description. [0032] As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. The term "a nucleic acid molecule” includes a plurality of nucleic acid molecules.
  • the term “comprising” is intended to mean that the ALK-7 antibodies and methods include the recited elements, but do not exclude other elements.
  • Consisting essentially of when used to define ALK-7 antibodies and methods, shall mean excluding other elements of any essential significance to the combination.
  • an anti-ALK-7 antibody consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the ALK- 7 antibody of this invention. Embodiments defined by each of these transition terms are within the scope of this invention.
  • polynucleotide and “nucleic acid molecule” are used interchangeably to refer to polymeric forms of nucleotides of any length.
  • the polynucleotides may contain deoxyribonucleotides, ribonucleotides, and/or their analogs.
  • Nucleotides may have any three-dimensional structure, and may perform any function, known or unknown.
  • polynucleotide includes, for example, single-, double-stranded and triple helical molecules, a gene or gene fragment, exons, introns, mRNA, tRNA, rRNA, ribozymes, antisense molecules, cDNA, recombinant polynucleotides, branched polynucleotides, aptamers, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • a nucleic acid molecule may also comprise modified nucleic acid molecules (e.g., comprising modified bases, sugars, and/or internucleotide linkers).
  • peptide refers to a compound of two or more subunit amino acids, amino acid analogs, or peptidomimetics. The subunits may be linked by peptide bonds or by other bonds (e.g., as esters, ethers, and the like).
  • amino acid refers to either natural and/or unnatural or synthetic amino acids, including glycine and both D or L optical isomers, and amino acid analogs and peptidomimetics. A peptide of three or more amino acids is commonly called an oligopeptide if the peptide chain is short.
  • the peptide chain is long (e.g., greater than about 10 amino acids), the peptide is commonly called a polypeptide or a protein. While the term “protein” encompasses the term “polypeptide”, a “polypeptide” may be a less than full-length protein. [0039] As used herein, "expression” refers to the process by which polynucleotides are transcribed into mRNA and/or translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA transcribed from the genomic DNA.
  • variant refers to a polypeptide that possesses a similar or identical function as an anti-ALK-7 antibody, but does not necessarily comprise a similar or identical amino acid sequence of an anti-ALK-7 antibody or possess a similar or identical structure of an anti-ALK-7 antibody.
  • a variant having a similar amino acid refers to a polypeptide that satisfies at least one of the following: (a) a polypeptide comprising, or alternatively consisting of, an amino acid sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the amino acid sequence of an anti- ALK-7 antibody (including a VH domain, CDRH1-3, VL domain, or CDRL1-3) having an amino acid sequence of any one of those referred to in Tables 1-4); (b) a polypeptide encoded by a nucleotide sequence, the complementary sequence of which hybridizes under stringent conditions to a nucleotide sequence encoding an anti-ALK-7 antibody (including a VH domain, CDRH1-3, VL domain, or CDRL1-3) having an amino acid sequence
  • Preferred scFV anti-ALK-7 antibodies comprise the VL and VH domains of the same antibody selected from antibodies identified in column 1 (“AntibodyID”) in Table 1. See Carter (2006) Nature Rev. Immunol.6:243. It is understood that linkages can vary, so long as the VL and VH domains are linked in a way maintain functionality of the anti-ALK-7 antibodies.
  • the immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.
  • the anti-ALK-7 antibodies are human antibodies comprising the sequences described in any one of the Tables 1-4.
  • "human" antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries and xenomice or other organisms that have been genetically engineered to produce human antibodies.
  • “Humanized” or chimeric anti-ALK-7 monoclonal antibodies as described in Tables 1- 4 can be produced using techniques described herein or otherwise known in the art. For example, standard methods for producing chimeric antibodies are known in the art. See, for review the following references: Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S.
  • the anti-ALK-7 antibodies provided herein may be monovalent, bivalent, trivalent or multivalent.
  • monovalent scFvs can be multimerized either chemically or by association with another protein or substance.
  • a scFv that is fused to a hexahistidine tag or a Flag tag can be multimerized using Ni-NTA agarose (Qiagen) or using anti-Flag antibodies (Stratagene, Inc.). Additionally, monospecific, bispecific, trispecific or of greater multispecificity for ALK-7 antigen(s) can also be generated. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol.147:60-69 (1991); U.S. Patent Nos.
  • a DutaMab is a type of bispecific antibody invented by Dutalys (acquired by Roche). This platform differs by developing fully human bispecific antibodies that show high affinity in each arm and simultaneously bind both targets.
  • CD47 also known as Integrin Associated Protein, is a transmembrane receptor that belongs to the immunoglobulin superfamily and is ubiquitously expressed on the surface of normal and solid tumor cells. CD47 is also involved in numerous normal and pathological processes including immunity, apoptosis, proliferation, migration, and inflammation. Previous studies have demonstrated the expression of CD47 on various cancer cells and revealed its role in promoting cancer progression. By binding with signal regulatory protein (SIRP ⁇ ), the primary ligand of CD47 expressed on phagocytic cells (dendritic cells, macrophages, and neutrophils), CD47 prohibits phagocytosis and thus allows tumor cells to evade immune surveillance. Thus, CD47 appears as an important therapeutic target for cancer treatments.
  • SIRP ⁇ signal regulatory protein
  • the following peptides can be used to raise antibodies to ALK-7: >Chain-1 ALK7 ECD monomer IgG1 Fc Fusion Protein (Hole) MEWSWVFLFFLSVTTGVHSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPG GGGGSDYKDDDDKGGGGSGLNDIFEAQKIEWHE (SEQ ID NO:197) >Chain-2 ALK7 ECD monomer IgG1 Fc Fusion Protein (Knob)
  • partially human refers to a nucleic acid having sequences from both a human and a non-human vertebrate.
  • the partially human nucleic acids have sequences of human immunoglobulin coding regions and sequences based on the non-coding sequences of the endogenous immunoglobulin region of the non-human vertebrate.
  • transgenic animal is meant a non-human animal, usually a mammal, having an exogenous nucleic acid sequence present as an extrachromosomal element in a portion of its cells or stably integrated into its germ line DNA (i.e., in the genomic sequence of most or all of its cells).
  • a transgenic animal comprising human sequences
  • a partially human nucleic acid is introduced into the germ line of such transgenic animals by genetic manipulation of, for example, embryos or embryonic stem cells of the host animal according to methods well known in the art.
  • a "vector” includes plasmids and viruses and any DNA or RNA molecule, whether self- replicating or not, which can be used to transform or transfect a cell.
  • a “genetic modification” refers to any addition, deletion or disruption to a cell's normal nucleotides.
  • Art recognized methods include viral mediated gene transfer, liposome mediated transfer, transformation, transfection and transduction, e.g., viral-mediated gene transfer using adenovirus, adeno-associated virus and herpes virus, as well as retroviral based vectors.
  • a “PD-1 signaling inhibitor” is an exogenous factor, such as a pharmaceutical compound or molecule that inhibits or prevents the activation of PD-1 by its ligand PD-L1 and thereby blocks or inhibits PD-1 signaling in cells within the cancerous tumor.
  • a “PD-L1 antagonist” is defined as a molecule that inhibits PD-1 signaling by binding to or inhibiting PD-L1 from binding and/or activating PD-1, thereby inhibiting PD-1 signaling and/or enhancing T-cell activation.
  • Preferred examples of a PD-L1 antagonist include, but are not limited to an anti-PD-L1 antibody which are well known in the art. See, Brahmer, et al. NEJM 2012.
  • anti-CXCL12 antibody or a “CXC12 antagonist” is defined as a monoclonal antibody or small molecule that exclusively recognizes the antigen, CXCL12, and thereby elicits immune responses, such as Fc receptor-mediated phagocytosis and antibody- dependent cell-mediated cytotoxicity.
  • Preferred examples of anti-CXCL12 antibodies include, but are not limited to, MAB310 (R&D Systems) and hu30D8.
  • an “anti-CXCR4 antibody” or a “CXCR antagonist” is defined as a monoclonal antibody or small molecule that exclusively recognizes the CXCR4 receptor on T cells and thereby elicits immune responses, such as Fc receptor-mediated phagocytosis and antibody-dependent cell-mediated cytotoxicity.
  • anti-CXCR4 inhibitors include AMD3100, BMS-936564/MDX-1338, AMD11070, or LY2510924.
  • CAR T-cells also known as chimeric antigen receptor T-cells
  • T-cells are produced by using adoptive cell transfer technique. T-cells are first collected from patients’ blood and recombinant receptors are introduced into these T-cells using genetic engineering methods such as retroviruses. CAR T-cells are then infused into the patient, the tumor-associated antigen is recognized by the CAR T-cell, and is destroyed. Thus, CAR T-cells enhance tumor specific immunosurveillance.
  • CAR most commonly incorporates a single-chain variable fragment (scFv) derived from a monoclonal antibody that links to intracellular signaling domains and forms a single chimeric protein.
  • scFv single-chain variable fragment
  • the CAR T-cell is developed using scFV, variable regions or CDRs as described herein.
  • the ALK-7-targeted immune response agent of the present invention whether it be an anti-ALK-7 antibody (e.g., a bispecific anti-ALK-7 antibody), a CAR T-cell engineered to express a chimeric antigen receptor comprising the anti-ALK-7 antibody sequences described herein, or a T-cell preloaded with anti-ALK-7 antibodies sequences, has synergistic activity with a second molecule co-administered with the anti-ALK-7 targeted agent.
  • an anti-ALK-7 antibody e.g., a bispecific anti-ALK-7 antibody
  • a CAR T-cell engineered to express a chimeric antigen receptor comprising the anti-ALK-7 antibody sequences described herein, or a T-cell preloaded with anti-ALK-7 antibodies sequences has synergistic activity with a second molecule co-administered with the anti-ALK-7 targeted agent.
  • a “T-cell co-receptor” is a cell surface receptor that binds to ligands on antigen-presenting cells that are distinct from the peptide-MHC complex that engages the T-cell receptor. Ligation of T-cell co-receptors enhance the antigen-specific activation of the T-cell by recruiting intracellular signaling proteins (e.g., NFkappaB and PI3-kinase) inside the cell involved in the signaling of the activated T lymphocyte.
  • intracellular signaling proteins e.g., NFkappaB and PI3-kinase
  • Preferred embodiments of a T-cell co- receptor antagonist include, but are not limited to anti-T-cell co-receptor antibodies, such as, for example, antibodies directed to 4-1BB(CD137) and ICOS (CD278).
  • the present invention encompasses the anti-ALK-7 antibody amino acid sequences described in Tables 1-4.
  • Tables 1-4 describe the domains of both the heavy and light chains of 11 different anti- ALK-7 antibodies. Specifically, Table 1 provides the names of each heavy chain (“Heavy_chain_id”) and light chain (“Light_chain_id”) variable domains making up each antibody identified by “AntibodyId” (also labeled as ”Ab_Num_Id” as used in Figure 1).
  • Table 2 provides the amino acid sequences making up each of the three complementarity-determining regions (“CDRs”) for each heavy and light chains (the CDRs identified in Table 2 as “CDR1,” “CDR2”, and “CDR3”) for the antibodies described herein.
  • CDRs complementarity-determining regions
  • Table 2 also groups the obtained heavy and light chain antibody sequences into “clusters” or “clades” based on the overall similarity of the full length sequences for certain antibodies that are related to one another. From these clusters, consensus sequences for each domain (FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4) for both the heavy and light chains) are created and shown.
  • These antibody variants have at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any of the amino acid sequences identified in Tables 1-4.
  • These variant antibodies must retain the ability to bind to ALK-7.
  • the variants comprise the CDRs described in Tables 2 and 4.
  • Preferred vectors include those which have already been used as live vaccines, such as vaccinia. These recombinants can be directly inoculated into a host, conferring immunity not only to the microbial vector, but also to express the anti-ALK-7 antibodies described herein.
  • Preferred vectors contemplated herein as live recombinant vaccines include RNA viruses, adenovirus, herpesviruses, poliovirus, and vaccinia and other pox viruses, as taught in Flexner, Adv. Pharmacol.21: 51, 1990, for example.
  • a eukaryotic expression vector preferably includes a heterologous, homologous, or chimeric promoter for RNA polymerase II, a downstream polyadenylation signal, the start codon AUG, and a termination codon for detachment of a ribosome.
  • Expression control sequences may be obtained from naturally occurring genes or may be designed. Designed expression control sequences include, but are not limited to, mutated and/or chimeric expression control sequences or synthetic or cloned consensus sequences. Vectors that contain both a promoter and a cloning site into which a polynucleotide can be operatively linked are well known in the art.
  • Suitable origins therefore include, but are not limited to, those which function in bacterial cells (e.g., such as Escherichia sp., Salmonella sp., Proteus sp., Clostridium sp., Klebsiella sp., Bacillus sp., Streptomyces sp., and Pseudomonas sp.), yeast (e.g., such as Saccharamyces sp. or Pichia sp.), insect cells, and mammalian cells.
  • an origin of replication is provided which functions in the target cell into which the vehicle is introduced (e.g., a mammalian cell, such as a human cell).
  • At least two origins of replication are provided, one that functions in a host cell and one that functions in a target cell.
  • the constructs comprising the polynucleotides encoding the anti-ALK-7 antibody as described herein may alternatively, or additionally, comprise sequences to facilitate integration of at least a portion of the polynucleotide into a target cell chromosome.
  • the construct may comprise regions of homology to target cell chromosomal DNA.
  • the construct comprises two or more recombination sites which flank a nucleic acid sequence encoding the polynucleotide encoding the anti-ALK-7 antibody described herein.
  • the vector may additionally comprise a detectable and/or selectable marker to verify that the vector has been successfully introduced in a target cell and/or can be expressed by the target cell.
  • markers can encode an activity, such as, but not limited to, production of RNA, peptide, or protein, or can provide a binding site for RNA, peptides, proteins, inorganic and organic compounds or compositions and the like.
  • the anti-ALK-7 antibody constructs according to the invention can be expressed in a variety of host cells, including, but not limited to: prokaryotic cells (e.g., E.
  • anti-ALK-7 antibody constructs are expressed in a transgenic organism (e.g., a transgenic mouse, rat, rabbit, pig, primate, etc.) that comprises somatic and/or germline cells comprising nucleic acids encoding the anti-ALK-7 antibody constructs.
  • a transgenic organism e.g., a transgenic mouse, rat, rabbit, pig, primate, etc.
  • Methods for constructing transgenic animals are well known in the art and are routine.
  • the anti-ALK-7 antibody constructs also can be introduced into cells in vitro, and the cells (e.g., such as stem cells, hematopoietic cells, lymphocytes, and the like) can be introduced into the host organism.
  • the cells may be heterologous or autologous with respect to the host organism.
  • the vector(s) for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art.
  • methods for preparing an anti-ALK-7 antibody described herein can occur simply by expressing a polynucleotide encoding the anti-ALK-7 antibody described in Tables 1-4 using techniques well known in the art.
  • the invention provides replicable vectors comprising a nucleotide sequence encoding the anti-ALK-7 antibody obtained and isolated as described herein (e.g., a whole antibody, a heavy or light chain of an antibody, a heavy or light chain variable domain of an antibody, or a portion thereof, or a heavy or light chain CDR, a single chain Fv, or fragments or variants thereof), operably linked to a promoter.
  • a nucleotide sequence encoding the anti-ALK-7 antibody obtained and isolated as described herein (e.g., a whole antibody, a heavy or light chain of an antibody, a heavy or light chain variable domain of an antibody, or a portion thereof, or a heavy or light chain CDR, a single chain Fv, or fragments or variants thereof), operably linked to a promoter.
  • bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, are used for the expression of the anti-ALK-7 antibody.
  • mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).
  • CHO Chinese hamster ovary cells
  • a vector such as the major intermediate early gene promoter element from human cytomegalovirus
  • a number of expression vectors may be advantageously selected depending upon the intended use.
  • pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST).
  • GST glutathione 5-transferase
  • fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione.
  • the pGEX vectors are designed to include thrombin or Factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
  • AcNPV Autographa califomica nuclear polyhedrosis virus
  • This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination.
  • Insertion in a non-essential region of the viral genome e.g., region El or E3 will result in a recombinant virus that is viable and capable of expressing the anti-ALK-7 antibody(e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)).
  • Specific initiation signals may also be required for efficient translation of inserted coding sequences. These signals include the ATG initiation codon and adjacent sequences.
  • initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert.
  • exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic.
  • the efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., Methods in Enzymol.153:51-544 (1987)).
  • a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired.
  • Tumor therapy includes using the anti-ALK-7 antibody described herein to reduce the rate of tumor growth, that is slow down, but not necessarily eliminate all tumor growth. Reduction in the rate of tumor growth can be, for example, a reduction in at least 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200% or more of the rate of growth of a tumor.
  • tumor antigens that may be expressed include, for example, overexpressed or mutated proteins and differentiation antigens particularly melanocyte differentiation antigens such as p53, ras, CEA, MUC1, PMSA, PSA, tyrosinase, Melan-A, MART-1, gp100, gp75, alpha-actinin- 4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-2, and 3, neo-PAP, myosin class I, OS-9, pml- RAR.alpha.
  • melanocyte differentiation antigens such as p53, ras
  • tumor antigens that may be expressed are well-known in the art (see for example WO00/20581; Cancer Vaccines and Immunotherapy (2000) Eds Stern, Beverley and Carroll, Cambridge University Press, Cambridge)
  • the sequences of these tumor antigens are readily available from public databases but are also found in WO 1992/020356 A1, WO 1994/005304 A1, WO 1994/023031 A1, WO 1995/020974 A1, WO 1995/023874 A1 & WO 1996/026214 A1.
  • the anti-ALK-7 antibody as described herein may be administered together with other cancer, diabetic and/or obesity drugs approved by the FDA.
  • the anti-ALK-7 antibody as described herein may also be administered together with other anti-cancer therapies, such as conventional chemotherapeutic agents, radiation therapy or cancer immunotherapy.
  • the anti-ALK-7 antibody is administered together with an anti-cancer compound.
  • the anti-ALK-7 antibody and the anti-cancer compound may be separate compounds or molecules or they may be covalently or non-covalently linked in a single compound, molecule, particle or complex.
  • An anti-cancer compound may be any anti-cancer drug or medicament which has activity against cancer cells.
  • Suitable anti-cancer compounds for use in combination with the anti- ALK-7 antibody as disclosed herein may include aspirin, sulindac, curcumin, alkylating agents including: nitrogen mustards, such as mechlor-ethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil; nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU); thylenimines/methylmelamine such as thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DTIC); antimetabolites including folic acid analogs such as methotrexate and trimetrexate, pyrimidine analogs such as 5-fluorouracil, fluorodeoxyuridine, gemcita
  • compositions may further contain auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like.
  • one or both of the anti-ALK-7 antibody and the anti-cancer or anti-obesity compound may be provided in a lyophilized form for reconstitution prior to administration.
  • lyophilized reagents may be re-constituted in sterile water and mixed with saline prior to administration to a subject
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • treatment as a prophylactic measure is also included.
  • a subject susceptible to or at risk of the occurrence or re-occurrence of cancer may be treated as described herein. Such treatment may prevent or delay the occurrence or re-occurrence of cancer in the subject.
  • the anti-ALK-7 antibody may be administered as described herein in therapeutically- effective amounts.
  • the term “therapeutically-effective amount” as used herein pertains to that amount of an active compound, or a combination, material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio. It will be appreciated that appropriate dosages of the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the administration.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the route of administration, the time of administration, the rate of excretion of the active compound, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of active compounds and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve concentrations of the active compound at a site of therapy without causing substantial harmful or deleterious side-effects.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day.
  • an anti-ALK-7 antibody as described herein such as such as, for example, a bispecific anti-ALK-7 antibody, a scFV antibody, or CAR T-cells may be administered by continuous intravenous infusion in an amount sufficient to maintain the serum concentration at a level that inhibits tumor growth.
  • Other anti-ALK-7 targeted agents described herein can also be used in this same manner.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals).
  • Administration of anti-cancer compounds and the anti-ALK-7 antibody may be simultaneous, separate or sequential.
  • simultaneous administration it is meant that the anti- cancer compounds and the anti-ALK-7 antibody are administered to the subject in a single dose by the same route of administration.
  • separatate it is meant that the anti-cancer compounds and the anti-ALK-7 antibody are administered to the subject by two different routes of administration which occur at the same time.
  • the anti-cancer compounds and the anti-ALK-7 antibody are administered at different points in time, provided that the activity of the first administered agent is present and ongoing in the subject at the time the second agent is administered.
  • the anti-cancer compounds may be administered first, such that an immune response against a tumor antigen is generated, followed by administration of the anti- ALK-7 antibody, such that the immune response at the site of the tumor is enhanced, or vice versa.
  • Multiple doses of the anti-cancer compounds may be administered, for example 2, 3, 4, 5 or more than 5 doses may be administered after administration of the ALK-7-targeted immune response agent.
  • the administration of the anti-cancer compounds may continue for sustained periods of time after administration of the anti-ALK-7 antibody.
  • treatment with the anti-cancer compounds may be continued for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month or at least 2 months. Treatment with the anti-cancer compounds may be continued for as long as is necessary to achieve complete tumor rejection.
  • the active compounds or pharmaceutical compositions comprising the active compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); and parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
  • oral e.g. by ingestion
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, sub
  • compositions comprising the active compounds may be formulated in suitable dosage unit formulations appropriate for the intended route of administration.
  • Formulations suitable for oral administration e.g.
  • a tablet may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface- active or dispersing or wetting agents (e.g.
  • binders e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose
  • fillers or diluents e.g. lactose, microcrystalline cellulose, calcium
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Preferred formulations for anti-ALK-7 antibody delivery include formulations suitable for parenteral administration (e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), and include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • parenteral administration e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal
  • aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives
  • Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer’s Solution, or Lactated Ringer’s Injection.
  • concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Suitable cancer vaccines are known in the art and may be produced by any convenient technique.
  • the use of tumor antigens to generate immune responses is well-established in the art (see for example; Kakimi K, et al. Int J Cancer.2011 Feb 3; Kawada J, Int J Cancer.2011 Mar 16; Gnjatic S, et al. Clin Cancer Res.2009 Mar 15;15(6):2130-9; Yuan J, et al. Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20410-5; Sharma P, et al. J Immunother. 2008 Nov- Dec;31(9):849-57; Wada H, et al.
  • Cancer cells from the subject may be analyzed to identify a tumor antigen expressed by the cancer cells.
  • a method as described herein may comprise the step of identifying a tumor antigen which is displayed by one or more cancer cells in a sample obtained from the subject.
  • a cancer vaccine comprising one or more epitopes of the identified tumor antigen may then be administered to the subject whose cancer cells express the antigen.
  • the vaccine may induce or increase an immune response, preferably a T-cell mediated immune response, in the subject against the cancer cells expressing the identified tumor antigen.
  • the cancer vaccine may be administered before, at the same time, or after the anti- ALK-7 antibody is administered to the subject as described here.
  • Adoptive T-cell therapy involves the administration to a subject of tumor-specific T- cells to a subject.
  • the T-cells were previously isolated from the subject and expanded ex vivo.
  • Suitable adoptive T-cell therapies are well known in the art (J. Clin Invest.2007 June 1; 117(6): 1466–1476.)
  • adoptive T-cell therapy using CAR T-cells would be greatly improved if used in combination with an anti-ALK-7 antibody.
  • CAR T- cells must migrate into a tumor to get in proximity to the cancer cells within the tumor in order to mediate their killing activity.
  • the treatment of an individual using an anti-ALK-7 antibody may further comprise administering one or more tumor therapies to treat the cancerous tumor.
  • Such therapies include, for example, tumor medicaments, radiation and surgical procedures.
  • a tumor medicament is an agent which is administered to a subject for the purpose of treating a cancer.
  • Suitable medicaments for the treatment of tumors are well known in the art.
  • Suitable medicaments for use in combination with an anti-ALK-7 antibody as disclosed herein may include aspirin, sulindac, curcumin, alkylating agents including: nitrogen mustards, such as mechlor-ethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil; nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU); thylenimines/methylmelamine such as thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DTIC); antimetabolites including
  • aspects and embodiments of the invention relating to an anti-ALK-7 antibody and optionally one or more other agents disclosed above include disclosure of the administration of the compounds or agents separately (sequentially or simultaneously) or in combination (co-formulated or mixed).
  • the specification further discloses a composition comprising the anti-ALK- 7 antibody and optionally one or more other agents co-formulated or in admixture with each other and further discloses a kit or unit dose containing the anti-ALK-7 antibody.
  • such compositions, kits or doses further comprise one or more carriers in admixture with the agent or co-packaged for formulation prior to administration to an individual.
  • a check-point inhibitor such as a PD-1 signaling inhibitor, and an anti-ALK-7 antibody.
  • Aspects and embodiments of the invention relating to combinations of a PD-1 signaling inhibitor and anti-ALK- 7 antibody and optionally one or more other agents disclosed above include disclosure of the administration of the compounds or agents separately (sequentially or simultaneously) or in combination (co-formulated or mixed).
  • compositions comprising the PD-1 signaling inhibitor and anti-ALK-7 antibody and optionally one or more other agents co-formulated or in admixture with each other and further discloses a kit or unit dose containing the PD-1 signaling inhibitor and anti-ALK-7 antibody packaged together, but not in admixture.
  • compositions, kits or doses further comprise one or more carriers in admixture with one or both agents or co-packaged for formulation prior to administration to a subject.
  • Example 1 Measurement of ALK-7 Binding Affinity via ELISA
  • Human ALK-7 protein His-Tag
  • Anti-mouse IgG2a-HRP was from Southern Biotech (Birmingham, AL).
  • KPL Sure Blue Tetramethylbenzidine (TMB) substrate and TMB stop solution were from Seracare (Milford, MA).
  • MaxiSorp microtiter plate was bought from MilliporeSigma (St. Louis, MO).
  • H3PO4:ddH2O H3PO4:ddH2O
  • Injected analyte concentrations were from 100 nM down to 1.5625 nM, two-fold dilutions. All analytes were injected in duplicate. Sensorgrams from the overnight kinetics was evaluated by using 1:1 kinetics model fitting.
  • Tumor growth and survival were measured over time using digital calipers. Tumor area was calculated as (width 2 x length)/2. Mice were euthanized when tumors reached a size of 2000mm 3 or 20mm in any direction, when tumors had ulcerations greater than 2mm, or when mice showed distress or signs of peritoneal tumors, indicating that the tumor had grown through the peritoneal wall. All remaining (tumor-free) mice were euthanized on day 64 post tumor injection. Data was collected and graphed using Microsoft Excel and GraphPad Prism 10 software.
  • mice were then randomized to either standard chow or high-fat diet (Research Diets D12492, 60% kcal fat) groups. Food was provided ad libitum except during measurement of fasting blood glucose. Mice were maintained on diet with no additional treatment for a period of four weeks before the initial antibody treatment.
  • All antibodies were generated as described herein. Specifically, BioMetas (Shanghai, China) generated the antibodies and shipped to ITI at a concentration of 1mg/ml in formulation buffer (20mM Tris, 6% (w/w) sucrose, 0.05% PS-80, pH 7.4). Antibodies 5, 8, and 11 were tested in this study, but the remaining antibodies can also be tested as described.
  • Antibodies 8 and 11 showed the most consistent in vivo anti-tumor effects, while antibody 5 showed the lowest KD values as measured by SPR. Specifically, antibody treatments were given three times per week (Monday/Wednesday/Friday) starting on day 28 post the start of high-fat diet by injecting 100 ⁇ g (100 ⁇ l) of each appropriate antibody intraperitoneally. PBS was used in groups A (standard chow) and B (high-fat diet) as a negative control. [0213] Weight and fasting blood glucose measurements. Animals were weighed on day 0, day 28, and three times per week following day 28 and coinciding with antibody treatments. Every 14 days, fasting blood glucose was measured. Animals were fasted overnight prior to blood collection from the tail.

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Abstract

La présente demande concerne des anticorps spécifiques qui se lient à ALK-7. La demande concerne également des utilisations de ces anticorps, des procédés de fabrication de ces anticorps et de polynucléotides et des cellules hôtes associées à ces anticorps.
PCT/US2025/012396 2024-01-19 2025-01-21 Anticorps de récepteur du récepteur anti-activine 1c (alk-7) Pending WO2025155971A1 (fr)

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