WO2019146588A1 - Anticorps anti-lck-486 et composition de traitement du cancer comprenant celui-ci - Google Patents

Anticorps anti-lck-486 et composition de traitement du cancer comprenant celui-ci Download PDF

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WO2019146588A1
WO2019146588A1 PCT/JP2019/001838 JP2019001838W WO2019146588A1 WO 2019146588 A1 WO2019146588 A1 WO 2019146588A1 JP 2019001838 W JP2019001838 W JP 2019001838W WO 2019146588 A1 WO2019146588 A1 WO 2019146588A1
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antibody
seq
amino acid
acid sequence
lck
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PCT/JP2019/001838
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Japanese (ja)
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智子 松枝
伊東　恭悟
七條　茂樹
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学校法人 久留米大学
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    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present disclosure relates to an antibody against a CTL epitope peptide of a cancer antigen protein, a composition for cancer treatment containing the same, and the like.
  • Lck is a Src family non-receptor protein tyrosine kinase that is expressed in activated T cells and metastatic cancer cells. While Lck is involved in normal development and activation of T cells, it is also known as a cancer antigen protein, and several Lck-derived CTL epitope peptides that can be used as cancer vaccines have been reported. In addition, it has been reported that antibodies against Lck-derived CTL epitope peptides are present in the sera of healthy people and cancer patients before vaccine administration, and that levels of anti-peptide antibodies after vaccine administration are correlated with patient survival time. There is. However, the biological function of antibodies against CTL epitope peptides is not clear.
  • the present disclosure aims to clarify the function of an antibody against a CTL epitope peptide of a cancer antigen protein and to provide its use.
  • the present disclosure relates to a composition for treating cancer, comprising as an active ingredient an antibody or antibody fragment that binds to a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1).
  • the disclosure is an antibody or antibody fragment that binds to a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1), wherein the amino acid sequence of CDR1, SEQ ID NO: 5 comprising the amino acid sequence of SEQ ID NO: 4 A heavy chain variable region comprising CDR2 comprising the amino acid sequence of SEQ ID NO: 6; and CDR1 comprising the amino acid sequence of SEQ ID NO: 10, CDR2 comprising the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 12
  • the present disclosure provides a composition for cancer treatment comprising an antibody or antibody fragment against Lck CTL epitope peptide, and an antibody or antibody fragment usable for the composition.
  • FIG. 1 shows the results of confirmation of the specificity of anti-Lck-486 monoclonal antibody (mAb) (left) and anti-SART3-109 mAb (right) by a competition assay.
  • FIG. 2 shows the anti-tumor effect of anti-Lck-486 mAb in a mouse tumor model.
  • Vac Lck-486 and Vac SART2-161 show administration of Lck-486 peptide and SART2-161 peptide, respectively
  • mAb Lck-486 shows administration of anti-Lck-486 mAb (the same in FIG. 3).
  • FIG. 3 shows the adjuvant effect of anti-Lck-486 mAb in a mouse tumor model.
  • FIG. 4 shows changes in CD4 + T cells and CD8 + T cells in tumor infiltrating lymphocytes.
  • VC Lck486)
  • VC SART2-161
  • mAb Lck486
  • FIG. 5 shows changes in CD4 + CD25 + Foxp3 + Tregs subsets in tumor infiltrating lymphocytes.
  • FIG. 6 shows the effect of anti-Lck 486 mAb on dendritic cell maturation.
  • FIG. 7 shows the effect of anti-Lck 486 mAb on peptide specific CTL induction. The numerical value of each sample indicates the number of IFN- ⁇ producing cells (spots).
  • amino acid residues are represented by the following abbreviations.
  • Ala or A alanine Arg or R: arginine Asn or N: asparagine Asp or D: aspartic acid Cys or C: cysteine Gln or Q: Glutamine Glu or E: glutamate Gly or G: glycine His or H: histidine Ile or I: isoleucine Leu or L: leucine Lys or K: lysine Met or M: methionine Phe or F: phenylalanine Pro or P: Proline Ser or S: serine Thr or T: Threonine Trp or W: Tryptophan Tyr or Y: Tyrosine Val or V: valine
  • Lck-486 peptide refers to a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1), which corresponds to the amino acid sequence of amino acids 486-494 of Lck protein (SEQ ID NO: 2).
  • Lck-486 peptide and the “peptide consisting of the amino acid sequence of SEQ ID NO: 1” are synonymous.
  • antibody is meant to include various antibody structures, such as monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (eg, bispecific antibodies), etc. Used in The species of the antibody is not particularly limited, and examples include antibodies derived from mouse, rat, rabbit, goat and human.
  • antibody fragment means a molecule that contains a portion of an antibody as a component.
  • antibody fragments include, but are not limited to, antibody heavy and light chain variable regions (V H and V L ), F (ab ') 2 , Fab', Fab, Fv, disulfide-linked FV (sdFv), Single -Chain FV (scFV) and polymers of these.
  • the immunoglobulin class of the antibody is determined based on the heavy chain constant region.
  • the immunoglobulin classes include IgA, IgD, IgE, IgG, and IgM, and the corresponding heavy chains are referred to as ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ chains, respectively.
  • the immunoglobulin class of the antibody herein is not particularly limited. In one embodiment, the immunoglobulin class is an IgG.
  • the light chain of an antibody can be divided into kappa and lambda chains based on its constant region, but the antibody herein may have either kappa or lambda chain.
  • variable region of an antibody is usually composed of three complementarity determining regions (also referred to as CDRs) sandwiched between four framework regions (also described as FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Several methods have been reported to define antibody variable regions and CDRs, for example, the definition of Kabat based on sequence variability (Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. 1991), the definition of Chothia considering the position of structural loops (Chothia et al., J. Mol. Biol., 1987; 196: 901-917), a compromise between the Kabat definition and the Chothia definition.
  • an “antibody or antibody fragment that binds to Lck-486 peptide” refers to an antibody or antibody that binds to the peptide with an affinity sufficient to exert a desired effect (eg, antitumor effect or adjuvant effect) It means a fragment.
  • a desired effect eg, antitumor effect or adjuvant effect
  • an antibody or antibody fragment that binds to Lck-486 peptide is also described as “anti-Lck-486 antibody”.
  • the binding of the anti-Lck-486 antibody to the Lck-486 peptide can be confirmed by ELISA method, fluorescent antibody method, radioimmunoassay (RIA), BIACORE (registered trademark) surface plasmon resonance assay or the like.
  • the anti-Lck-486 antibody is an antibody or antibody in which the binding to the Lck-486 peptide measured by any of the above methods is significantly stronger than the binding to the control peptide, or not inhibited by the control peptide It is an antibody fragment.
  • Lck-488 peptide (DYLRSVLEDF) (SEQ ID NO: 3) can be used as a control peptide.
  • the anti-Lck-486 antibody is less than 10-8 M, such as 10-8 M to 10-13 M, 10-8 M to 10-12 M, 10-9 M to 10-12 M, or It has a dissociation constant (Kd) of 10 -9 M to 10 -11 M.
  • Binding affinity can be measured by radioimmunoassay (RIA), BIACORE® surface plasmon resonance assay or the like. In certain embodiments, binding affinity is measured by BIACORE® surface plasmon resonance assay. Whether or not the anti-Lck-486 antibody has a desired effect (for example, an antitumor effect or an adjuvant effect) can be confirmed according to the description of the examples.
  • Anti-Lck-486 antibody can be obtained by a general method by using Lck-486 peptide as an immunogen.
  • Lck-486 peptide can be produced by a conventional peptide synthesis method, for example, by genetic engineering or chemical synthesis.
  • Polyclonal antibodies can be prepared by the general method described in "Antibodies: A Laboratory Manual, Lane, H. D. et al. Eds., Cold Spring Harbor Laboratory Press, New York, 1989” and the like. Specifically, it can be produced by immunizing mammals such as rats, mice, rabbits, goats and horses with Lck-486 peptide.
  • a monoclonal antibody can be obtained by a known method such as a method of producing a hybridoma that produces an antibody, or a method of producing an expression vector containing an antibody gene using genetic engineering techniques and expressing it in cells.
  • Hybridomas secreting monoclonal antibodies can be prepared according to the method described in Kohler et al., Nature 256: 495, 1975. First, an immunogen is mixed with an appropriate substance (eg, keyhole limpet hemocyanin, bovine serum albumin, etc.) for enhancing antigenicity, and, if necessary, an immunostimulant (eg, Freund's complete or incomplete adjuvant). And immunize non-human mammals such as rats, mice, rabbits, goats and horses. Usually, the immunized animals are immunized several times at intervals of 3 to 10 days, and 1 to 100 ⁇ g of the immunogenic peptide is administered.
  • an immunogen eg, keyhole limpet hemocyanin, bovine serum albumin, etc.
  • an immunostimulant eg, Freund's complete or incomplete adjuvant
  • non-human mammals such as rats, mice, rabbits, goats and horses.
  • the immunized animals are immunized several times at intervals of 3 to
  • immunocompetent cells are recovered from the immunized animal which has undergone multiple immunizations, and myeloma cells (eg, mouse, rat, guinea pig, hamster, rabbit or The cells are fused with cells derived from mammals such as humans.
  • myeloma cells eg, mouse, rat, guinea pig, hamster, rabbit or The cells are fused with cells derived from mammals such as humans.
  • polyethylene glycol method, electrofusion method and the like are used.
  • select a cell that has succeeded in cell fusion based on the selection marker possessed by the fusion cell and confirm the reactivity of the antibody produced by the selected cell to the immunogen by ELISA, radioimmunoassay, fluorescent antibody method, etc.
  • Monoclonal antibodies can be isolated from culture supernatants obtained by culturing the obtained hybridomas in vitro. Alternatively, they can be cultured in vivo as ascites fluid such as mouse, rat, guinea pig, hamster or rabbit and isolated from ascites fluid.
  • a monoclonal antibody can also be obtained by cloning an antibody gene from the obtained hybridoma, incorporating it into an appropriate expression vector and expressing it in a host cell as described later (PJDelves., ANTIBODY PRODUCTION ESSENTIAL TECHNIQUES P. Shepherd and C. Dean., Monoclonal Antibodies., 2000 OXFORD UNIVERSITY PRESS; JW Goding., Monoclonal Antibodies: principles and practice., 1993 ACADEMIC PRESS).
  • a transgenic animal for example, cow, goat, sheep or pig
  • a monoclonal antibody derived from the antibody gene can also be obtained from
  • the obtained monoclonal antibody is purified by an appropriate combination of methods well known in the art, such as chromatography using a protein A column, ion exchange chromatography, hydrophobic chromatography, ammonium sulfate precipitation, gel filtration, affinity chromatography, etc. can do.
  • a chimeric antibody is an antibody containing different sequences derived from each other, for example, an antibody in which variable regions different from each other and a constant region are linked.
  • a chimeric antibody is composed of a variable region of an antibody derived from a non-human mammal and a constant region derived from a human antibody.
  • a chimeric antibody is prepared by linking a polynucleotide encoding a variable region of an antibody derived from a non-human mammal and a polynucleotide encoding a constant region of a human antibody, incorporating this into an expression vector, and using this expression vector as a host It can be obtained by introduction and expression.
  • CDRs are regions that substantially determine the binding specificity of an antibody, and the amino acid sequence is rich in diversity.
  • the amino acid sequences constituting the FR show high homology even between antibodies having different binding specificities. Therefore, by CDR grafting, the binding specificity of one antibody can be grafted to another antibody.
  • Humanized antibodies are generally composed of CDRs of antibodies derived from non-human animals and FRs derived from human antibodies and constant regions derived from human antibodies. Humanized antibodies can be obtained by grafting CDRs of non-human animal-derived antibodies into human antibodies. Humanized antibodies can be produced by various methods, and one example is Overlap Extension PCR (Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)).
  • PCR is performed using, as a primer, an oligonucleotide having a portion overlapping the end of the CDR of an antibody derived from a non-human animal (for example, a mouse antibody) and the end of the FR of a human antibody as a primer
  • a polynucleotide is synthesized in which the CDRs of the antibody and the FRs of a human antibody are linked.
  • the obtained polynucleotide is linked with a polynucleotide encoding a constant region of a human antibody, incorporated into an expression vector, and the expression vector is introduced into a host and expressed to obtain a humanized antibody. it can.
  • FRs suitable for producing humanized antibodies are known, and for example, FRs selected by the best fit method (Sims et al. J. Immunol. 151: 2296 (1993)), and light chains of human antibodies. Or FR derived from the consensus sequence of a particular subgroup of heavy chain variable regions (Carter et al. Proc. Natl. Acad. Sci. USA 89: 4285 (1992); Presta et al. J. Immunol. 151: 2623 ( 1993)) can be used.
  • Human antibodies can be obtained, for example, by sensitizing human lymphocytes with a desired antigen in vitro and then fusing the sensitized lymphocytes with human myeloma cells (Japanese Patent Publication No. 1-59878).
  • human myeloma cells Japanese Patent Publication No. 1-59878.
  • U266 or the like can be used for human myeloma cells that are fusion partners.
  • Human antibodies can also be obtained by immunizing transgenic animals carrying the entire repertoire of human antibody genes with the desired antigen (Lonberg, Nat. Biotech. 23: 1117-1125, 2005).
  • techniques for obtaining human antibodies by panning using a human antibody library are also known (Antibody Phage Display: Methods and Protocols, Methods in Molecular Biology 178, 2001).
  • variable region of a human antibody is expressed as a single chain antibody (scFv) on the surface of a phage by phage display method, a phage that binds to the antigen is selected, and the gene of the selected phage is analyzed to obtain an antigen.
  • the DNA sequence encoding the variable region of the human antibody to which it binds can be determined.
  • the variable region sequence is linked in frame to the sequence of a human antibody constant region, inserted into an appropriate expression vector, and the expression vector is introduced into a host and expressed to obtain a human antibody. it can.
  • Multispecific antibodies are antibodies that bind to at least two different sites. Multispecific antibodies include bispecific antibodies, trispecific antibodies and the like. In certain embodiments, multispecific antibodies bind the Lck-486 peptide and one or more other antigens. Multispecific antibodies can be produced, for example, by genetic engineering techniques, or by combining two or more antibodies or antibody fragments that have different recognition antigens.
  • An antibody fragment can be obtained, for example, by digesting an antibody with a protease such as papain or pepsin.
  • a protease such as papain or pepsin.
  • it can be obtained by introducing an expression vector containing a polynucleotide encoding an antibody fragment into a host cell and expressing it (eg, Co, M. S. et al., J. Immunol. (1994) 152, 2968).
  • an expression vector containing a polynucleotide encoding an antibody fragment into a host cell and expressing it (eg, Co, M. S. et al., J. Immunol. (1994) 152, 2968). -2976; Better, M. and Horwitz, A. H., Methods Enzymol. (1989) 178, 476-496; Pluckthun, A. and Skerra, A., Methods Enzymol. (1989) 178, 497-515; (1986) 121, 652
  • antibodies and antibody fragments can be obtained by introducing and expressing in cells an expression vector containing a polynucleotide encoding them.
  • an expression vector is constructed such that a sequence encoding an antibody or antibody fragment is expressed under an expression control region such as an enhancer or promoter, and the host cell is transformed with this expression vector to produce an antibody or antibody. The fragment is expressed.
  • the present disclosure also provides an expression vector comprising a polynucleotide encoding an antibody or antibody fragment that binds to Lck-486 peptide, and a transformed cell comprising a polynucleotide capable of expressing said antibody or antibody fragment.
  • eukaryotic cells such as animal cells, plant cells, and fungal cells can be used, for example.
  • animal cells mammalian cells (eg, CHO, COS, NIH3T3, myeloma, BHK (baby hamster kidney), HeLa, Vero), amphibian cells (eg, Xenopus oocytes), or insect cells (eg, Sf9, Sf21) , Tn5).
  • yeast for example, genus Saccharomyces, such as Saccharomyces cerevisiae
  • filamentous fungi for example, genus Aspergillus, such as Aspergillus niger
  • prokaryotic cells such as E. coli (eg, JM109, DH5 ⁇ , HB101, etc.), Bacillus subtilis can also be used as host cells.
  • the introduction of the vector into the host cell can be performed, for example, by the calcium phosphate method, the DEAE dextran method, the electroporation method, the lipofection and the like.
  • the binding of the obtained antibody or antibody fragment to Lck-486 peptide can be confirmed by ELISA, fluorescent antibody method, radioimmunoassay (RIA), BIACORE® surface plasmon resonance assay or the like.
  • Binding of the antibody or antibody fragment to the Lck-486 peptide can also be confirmed by a competition assay. For example, does the antibody or antibody fragment compete for binding to the Lck-486 peptide with an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13? This can be confirmed by examining it by FACS or ELISA.
  • the anti-Lck-486 antibody is A heavy chain variable region comprising the variable region of CDR1, CDR2 and CDR3 in the amino acid sequence of SEQ ID NO: 8 or the amino acid sequence of SEQ ID NO: 8; and CDR1, CDR2 and CDR3 in the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 14 And a light chain variable region comprising a variable region in the amino acid sequence of
  • CDRs 1-3 and variable regions may be defined in any way, including the definition of Kabat, the definition of Chothia, the definition of AdM, the definition of Contact, and the definition of IMGT.
  • CDRs 1-3 and variable regions are CDRs 1-3 and variable regions defined by any of the methods selected from Kabat definition, Chothia definition, AdM definition, Contact definition, and IMGT definition. is there.
  • the anti-Lck-486 antibody is A CDR1 comprising a sequence having a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more to the sequence of SEQ ID NO: 4, CDR2 comprising a sequence having a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more with the sequence of SEQ ID NO: 5, and 80% with the sequence of SEQ ID NO: 6
  • a CDR3 comprising a sequence having a sequence identity of at least 85%, more preferably at least 90%, even more preferably at least 95%;
  • / or a CDR1 comprising a sequence having a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more with the sequence of SEQ ID NO: 10
  • CDR2 comprising a sequence having a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or
  • Sequence identity is determined by comparing two sequences aligned in the optimal state over the entire region of the sequences to be compared.
  • the sequences to be compared may have additions or deletions (such as gaps) in the optimal alignment of the two sequences.
  • Sequence identity can be calculated using programs such as FASTA, BLAST, CLUSTAL W, etc. provided in public databases (eg, DDBJ (http://www.ddbj.nig.ac.jp)). Alternatively, it can be determined using commercially available sequence analysis software (for example, Vector NTI (registered trademark) software, GENETYX (registered trademark) ver. 12).
  • the sequence identity is 80% or more, preferably 85% or more, more preferably 90% or more, and still more preferably 95% or more.
  • the anti-Lck-486 antibody is A CDR1 comprising a sequence in which 0 to 2 amino acids have been deleted, substituted, or added in the sequence of SEQ ID NO: 4, CDR2 containing a sequence in which 0 to 2 amino acids have been deleted, substituted or added in the sequence of SEQ ID NO: 5, and 0 to 2 amino acids have been deleted, substituted or added in the sequence of SEQ ID NO: 6 CDR3, which contains a sequence And / or a CDR1 including a sequence in which 0 to 2 amino acids are deleted, substituted, or added in the sequence of SEQ ID NO: 10, CDR2 containing a sequence in which 0 to 2 amino acids have been deleted, substituted or added in the sequence of SEQ ID NO: 11, and 0 to 2 amino acids have been deleted, substituted or added in the sequence of SEQ ID NO: 12 CDR3, which contains a sequence A light chain variable region comprising including.
  • the anti-Lck-486 antibody has a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more of the amino acid sequence of SEQ ID NO: 7 And / or a sequence having a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or more, still more preferably 95% or more to the amino acid sequence of SEQ ID NO: 13 Comprising the light chain variable region.
  • the anti-Lck-486 antibody comprises a heavy chain variable region comprising an amino acid sequence wherein 0-2 amino acids have been deleted, substituted or added in the amino acid sequence of SEQ ID NO: 7, and / or A light chain variable region comprising an amino acid sequence in which 0 to 2 amino acids have been deleted, substituted or added in the 13 amino acid sequences.
  • an anti-Lck-486 antibody in which no change is made to the CDRs of the heavy chain variable region and / or the light chain variable region, specifically, CDR1 including the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5
  • a heavy chain variable region comprising CDR2 comprising the amino acid sequence and CDR3 comprising the amino acid sequence of SEQ ID NO: 6, and / or CDR1 comprising the amino acid sequence of SEQ ID NO: 10, CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and Included are anti-Lck-486 antibodies that contain a light chain variable region that contains a CDR3 that contains 12 amino acid sequences.
  • the anti-Lck-486 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13. In a further embodiment, the anti-Lck-486 antibody comprises a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 7 and / or a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 13.
  • mutants with improved binding affinity can be obtained by phage display based methods.
  • amino acid residues that affect the interaction between antibody and antigen are identified by alanine scanning mutagenesis, or the crystal structure of the antigen-antibody complex is analyzed to determine the contact point between antibody and antigen.
  • the mutation site is determined, for example, by identifying Mutants with altered amino acids at this site can be prepared by error prone PCR, site-directed mutagenesis and the like, and a library of the resulting mutants can be screened to obtain mutants with desired properties. .
  • the anti-Lck-486 antibody may have a modified sugar chain in the Fc region.
  • examples of antibodies whose sugar chains have been modified include an antibody lacking fucose to be added to sugar chains (US Patent Publication No. 2003/0157108), and an antibody having a sugar chain having bisect N-acetylglucosamine (GlcNAc) (international Publication No. 2003/011878) and the like.
  • the anti-Lck-486 antibody is conjugated to a polymer such as polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylene or a copolymer of polyethylene glycol and polypropylene glycol, for example to extend the half life of the antibody or improve the stability etc. It may be Anti-Lck-486 antibodies may also be conjugated to chemotherapeutic agents, toxic peptides, radiochemicals and the like.
  • a polymer such as polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylene or a copolymer of polyethylene glycol and polypropylene glycol, for example to extend the half life of the antibody or improve the stability etc. It may be Anti-Lck-486 antibodies may also be conjugated to chemotherapeutic agents, toxic peptides, radiochemicals and the like.
  • the anti-Lck-486 antibody can be used as an active ingredient of a composition for treating cancer.
  • the cancer therapeutic composition containing the anti-Lck-486 antibody as an active ingredient enhances the effects of the composition containing the anti-Lck-486 antibody as a component having antitumor activity and other agents.
  • compositions comprising as components (adjuvants) are included.
  • effective amount as used herein means an amount capable of exerting a desired effect (eg, antitumor effect or adjuvant effect).
  • Cancers include colon cancer, prostate cancer, brain cancer, pancreatic cancer, gastric cancer, lung cancer, uterine cancer, cervical cancer, thyroid cancer, liver cancer, esophageal cancer, melanoma, hematopoietic tumor (eg, leukemia, malignant lymphoma, Myeloma) and the like.
  • the cancer is colon cancer.
  • the dose of the anti-Lck-486 antibody is appropriately selected depending on the administration method, age of the administration subject, body weight, health condition and the like. For example, for adults, 10 ⁇ g / kg to 100 mg / kg, 100 ⁇ g / kg to 10 mg / kg, or 1 mg / kg to 10 mg / kg, once a day or several days or one week or several weeks, for example 1 to It can be administered once every three weeks, but is not limited thereto.
  • the method of administration of the antibody or antibody fragment is also appropriately selected according to the age, body weight, health condition and the like of the subject of administration.
  • the administration method may be oral administration or parenteral administration, but parenteral administration is preferred. Parenteral administration includes subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration and the like, preferably intravenous administration.
  • the composition can be formulated in a conventional manner.
  • the composition may comprise, in addition to the antibody or antibody fragment, sterile water, saline, stabilizers, excipients, excipients, antioxidants, buffers, preservatives, surfactants, chelating agents, binders, etc. it can.
  • Anti-Lck-486 antibodies can be used in conjunction with other cancer therapeutics or therapies.
  • Other cancer treatment methods or drugs include chemotherapy or chemotherapy drugs, immunotherapy or immunotherapeutic drugs, radiation therapy, surgery and the like.
  • the anti-Lck-486 antibody is used in combination with an immunotherapeutic or immunotherapeutic agent, such as a cancer vaccine therapy or cancer vaccine, dendritic cell vaccine therapy or dendritic cell vaccine, adoptive immunotherapy.
  • an anti-Lck-486 antibody is used in combination with a cancer peptide vaccine.
  • the "cancer peptide vaccine” in the present specification includes an agent containing a specific peptide and a personalized vaccine which selects a peptide to be administered for each patient.
  • the cancer peptide vaccine preferably comprises Lck-486 peptide.
  • two or more agents used "in combination" include the case where they are contained in the same composition and the case where they are contained in another composition, and also when they are administered simultaneously. It is also included when administered at different times.
  • the anti-Lck-486 antibody is prior to (eg, one, three, five, or seven days or more) administration of a cancer peptide vaccine (preferably a cancer vaccine comprising Lck-486 peptide) Before).
  • a cancer peptide vaccine preferably a cancer vaccine comprising Lck-486 peptide
  • the anti-Lck-486 antibody is administered after mixing with a cancer peptide vaccine, preferably a cancer vaccine comprising Lck-486 peptide.
  • the patient may be HLA-A24 positive when used in combination with a cancer vaccine containing Lck-486 peptide.
  • the anti-Lck-486 antibody can also be used for in vitro induction of cytotoxic T cells, dendritic cells and the like used for immune cell therapy.
  • a composition for cancer treatment containing an anti-Lck-486 antibody as an active ingredient is used for the external induction of cells used for the treatment of cancer (eg, cells for immunocell therapy).
  • a composition is included.
  • Anti-Lck-486 antibody is preferably used in combination with Lck-486 peptide in the induction of cells in vitro.
  • the anti-Lck-486 antibody is a cell (eg, peripheral blood mononuclear cells) prior to treatment (eg, 1 hour, 6 hours, 12 hours, or 24 hours or more) with Lck-486 peptide. To be treated.
  • the anti-Lck-486 antibody is treated to cells (eg, peripheral blood mononuclear cells) after mixing with Lck-486 peptide. When combined with Lck-486 peptide, cells may be HLA-A24 positive.
  • a composition for treating cancer which comprises, as an active ingredient, an antibody or antibody fragment that binds to a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1).
  • the antibody or antibody fragment is A composition according to the above 1, comprising a heavy chain variable region comprising CDR1, CDR2 and CDR3 in the amino acid sequence of SEQ ID NO: 8; and a light chain variable region comprising CDR1, CDR2 and CDR3 in the amino acid sequence of SEQ ID NO: 14. .
  • the antibody or antibody fragment is A composition according to claim 1 or 2, comprising a heavy chain variable region comprising a variable region in the amino acid sequence of SEQ ID NO: 8; and a light chain variable region comprising a variable region in the amino acid sequence of SEQ ID NO: 14.
  • the antibody or antibody fragment is A heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 4, CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and CDR3 comprising the amino acid sequence of SEQ ID NO: 6; and CDR1 comprising the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 10 11.
  • composition according to any of the preceding claims comprising a light chain variable region comprising CDR2 comprising 11 amino acid sequences and CDR3 comprising the amino acid sequence of SEQ ID NO: 12.
  • the antibody or antibody fragment is A heavy chain variable region comprising CDR1 consisting of the amino acid sequence of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of SEQ ID NO: 5, and CDR3 consisting of the amino acid sequence of SEQ ID NO: 6; and CDR1 consisting of the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 10 11.
  • composition according to any one of the above 1 to 4 comprising a light chain variable region comprising CDR2 consisting of 11 amino acid sequences and CDR3 consisting of the amino acid sequence of SEQ ID NO: 12.
  • the antibody or antibody fragment is A heavy chain variable region comprising a sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 7; and a light chain variable region comprising a sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 13
  • the antibody or antibody fragment is A heavy chain variable region comprising an amino acid sequence in which 0-2 amino acids have been deleted, substituted or added in the amino acid sequence of SEQ ID NO: 7; and 0-2 amino acids in the amino acid sequence of SEQ ID NO: 13 7.
  • the composition according to any of the above 1 to 7, wherein the antibody or antibody fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13.
  • composition according to any one of 1 to 8, wherein the antibody or antibody fragment comprises a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 13.
  • the composition according to any one of the above 1 to 9, wherein the antibody or antibody fragment is a monoclonal antibody.
  • the composition according to any one of the above 1 to 10 which is used in combination with a cancer peptide vaccine.
  • the cancer peptide vaccine comprises a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1).
  • the antibody or antibody fragment according to the above-mentioned 15, comprising a heavy chain variable region comprising a variable region in the amino acid sequence of SEQ ID NO: 8; and a light chain variable region comprising a variable region in the amino acid sequence of SEQ ID NO: 14.
  • a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 4, CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and CDR3 comprising the amino acid sequence of SEQ ID NO: 6; and CDR1 comprising the amino acid sequence of SEQ ID NO: 10
  • the antibody or antibody fragment according to 15 or 16 which comprises a light chain variable region comprising CDR2 comprising the amino acid sequence of SEQ ID NO: 11 and CDR3 comprising the amino acid sequence of SEQ ID NO: 12.
  • a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of SEQ ID NO: 5, and CDR3 consisting of the amino acid sequence of SEQ ID NO: 6; and CDR1 consisting of the amino acid sequence of SEQ ID NO: 10
  • a heavy chain variable region comprising a sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 7; and a light chain variable comprising a sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 13
  • a heavy chain variable region comprising an amino acid sequence in which 0 to 2 amino acids have been deleted, substituted or added in the amino acid sequence of SEQ ID NO: 7; and 0 to 2 amino acids in the amino acid sequence of SEQ ID NO: 13
  • the antibody or antibody fragment according to any of the above 15 to 19 comprising a light chain variable region comprising a deleted, substituted or added amino acid sequence.
  • the antibody or antibody fragment according to any of 15 to 20 which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13.
  • the antibody or antibody fragment according to any of the above 15 to 21 comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 13.
  • the antibody or antibody fragment described in any of the above 15-22 which is a monoclonal antibody.
  • An expression vector comprising a polynucleotide encoding the antibody or antibody fragment according to any of 15 to 23 above.
  • a transformed cell comprising a polynucleotide capable of expressing the antibody or antibody fragment of any of 15 to 23 above.
  • a method of treating cancer comprising administering to a subject an effective amount of an antibody or antibody fragment that binds to a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1).
  • the method according to the above 26, wherein the antibody or the antibody fragment is the antibody or the antibody fragment according to any of the 15 to 23 above.
  • the cancer peptide vaccine comprises a peptide consisting of the amino acid sequence of TFDYLRSVL (SEQ ID NO: 1).
  • the antibody or antibody fragment is the antibody or antibody fragment according to any of 15 to 23 above.
  • Lck-486 monoclonal antibody Lck-486 peptide (TFDYLSRVL) (SEQ ID NO: 1) (also described as Lck 486-494 ) and SART3-109 peptide (VYDYNCHVDL) (SEQ ID NO: 16) (also described as SART3 109-118 )
  • Hybridoma clones producing an IgG2b specific for X were generated at Cell Engineering Corp. (Osaka, Japan).
  • the amino acid sequence of amino acids 486 to 494 of Lck is common to mouse and human, but the amino acid sequence of amino acids 109 to 118 of SART 3 is E instead of D at amino acid 117 in mouse.
  • the specificity of the obtained antibody was confirmed by a competition assay (FIG.
  • Lck-488 peptide (DYLRSVLEDF) (SEQ ID NO: 3) (also described as Lck 488-497 ) and SART 3-309 peptide (RLAEYQAYI) (SEQ ID NO: 17) (SART 3) as control peptides of Lck-486 and SART 3-109 peptides 309-317 ) were used.
  • the hybridomas were cultured in serum-free hybridoma culture medium (Life Technologies, Carlsbad, CA), the supernatant was recovered, and the IgG was purified using a Protein-A column (GE Healthcare, Uppsala, Sweden).
  • Hybridomas I12-1F3, 2.08 ⁇ 10 7 cells producing anti-Lck-486 mAb were dissolved in TRIzol reagent (Invitrogen), RNA was extracted and purified, and total RNA was recovered.
  • RACE-cDNA was produced about 5 micrograms of total RNA using GeneRacer Kit (Invitrogen). The following experiment was performed using this RACE-cDNA as a template A. Touchdown PCR was performed using GeneRacer 5'-primer attached to the kit for cloning 5 'region (variable region) by 5'-RACE method and 3'-Gene specific primer (GSP) designed for antibody constant region .
  • GSP 3'-Gene specific primer
  • H-2K d Antitumor and adjuvant effects of anti-Lck-486 monoclonal antibody in vivo Colon26 cells (H-2K d ) (10 7 cells) were injected subcutaneously into the right flank of female BALB / c Crl Crlj mice (H-2K d ). It is known that the H-2K d molecule binds to an HLA-A24 restricted peptide.
  • Lck-486 or SART2-161 peptide (AYDFLYNYL) (SEQ ID NO: 18) (also described as SART2 161- 169 ) was subcutaneously administered to the inguinal region at 50 ⁇ g / mouse on Days 7, 10 and 13.
  • the Lck-486 peptide and the SART2-161 peptide are known to be HLA-A24 restricted peptides, and the sequences are common between mouse and human.
  • Anti-Lck-486 mAb or isotype control IgG2b (clone: MG2b-57) was intraperitoneally administered at 13.7 mg / mouse on Day 7, Day 10, and Day 13.
  • mice were divided into 6 groups, and intraperitoneal injection of anti-Lck 486 mAb alone, intraperitoneal injection of isotype control antibody alone, subcutaneous injection of Lck-486 peptide alone, and subcutaneous injection of Lck-486 peptide into 4 groups Intraperitoneal injection of anti-Lck 486 mAb was performed on Day 3, Day 7, Day 11, Day 15, Day 19, respectively.
  • TIL tumor-infiltrating lymphocytes
  • mice administered Lck-486 peptide and anti-Lck 486 mAb compared to mice administered SART 2-161 and anti-Lck 486 mAb (negative control), CD8 + T cells (FIG. 4) and CD4 + CD25 + A significant reduction of Foxp3 + Tregs (FIG. 5) was observed (p ⁇ 0.05).
  • a reduction in CD4 + T cells, CD8 + T cells (FIG. 4), and CD4 + CD25 + Foxp3 + Treg subsets (FIG. 5) was also observed with anti-Lck 486 mAb alone, compared to isotype controls. This result suggests that anti-Lck 486 mAb suppresses antitumor immunosuppression by reducing Treg and exerts an antitumor effect.
  • This immature DC (10 4 cells / well / 0.2 ml) was treated with anti-Lck-486 mAb alone; anti-SART3-109 mAb alone; isotype control antibody (IgG2b) (clone: MG2b-57) alone; anti-Lck-486 mAb + Lck-486 Anti-Lck-486 mAb + SART2-161 peptide; isotype control antibody + Lck-486 peptide; anti-SART3-109 mAb + SART3-109 peptide; Lck-486 peptide alone; or with SART3-109 peptide alone for 24 hours.
  • IgG2b isotype control antibody
  • IgG2b isotype control antibody
  • DCs are stained with FITC-CD11c, APC-CD40, PerCP / Cy5.5-CD80, and PE / Cy7-CD86 (BioLegend Japan, Tokyo), and FACSVerse flow cytometer (BD Biosciences, Moustain View, CA) and FlowJo It analyzed in (version 7.6.5).
  • FITC-CD11c FITC-CD11c
  • APC-CD40 PerCP / Cy5.5-CD80
  • PE / Cy7-CD86 BioLegend Japan, Tokyo
  • FACSVerse flow cytometer BD Biosciences, Moustain View, CA
  • the immune complex is prepared by incubating 60 minutes at 37 ° C. with 2 ⁇ g of peptide and 20 ⁇ g of antibody, and the antibody concentration is 13.8 ⁇ g / mL, 6.9 ⁇ g / mL, 1.73 ⁇ g / mL, 0.43 ⁇ g / mL, or 0.11. It was added to be ⁇ g / mL (FIG. 7, Lck-486 + mAb). After 4 days of culture, cells were harvested and tested for IFN- ⁇ production for Lck-486 peptide.
  • Antigen-specific IFN- ⁇ production after incubation for 18 hours was measured by ELISPOT.
  • ELISPOT As a result, in the cells stimulated with Lck-486 peptide + anti-Lck-486 mAb, a strong increase of IFN- ⁇ producing cells was observed (FIG. 7). An increase in IFN- ⁇ producing cells was also observed with Lck-486 peptide alone and anti-Lck-486 mAb alone.
  • Sequence number 1 Peptide sequence number 3: Peptide sequence number 4: Heavy chain CDR1 SEQ ID NO: 5: heavy chain CDR2 Sequence number 6: heavy chain CDR3 SEQ ID NO: 7: heavy chain variable region SEQ ID NO: 10: light chain CDR1 SEQ ID NO: 12: light chain CDR3 SEQ ID NO: 13: Light Chain Variable Region SEQ ID NO: 16: Peptide SEQ ID NO: 17: Peptide SEQ ID NO: 18: Peptide

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Abstract

La présente invention concerne une composition de traitement du cancer qui comprend un anticorps, ou un fragment de celui-ci, se liant à un peptide qui comporte comme principe actif la séquence d'acides aminés TFDYLRSVL (SEQ ID NO : 1) . La présente invention concerne également un anticorps, ou un fragment de celui-ci, se liant à un peptide comprenant la séquence d'acides aminés TFDYLRSVL (SEQ ID NO : 1), l'anticorps ou le fragment de celui-ci comprenant une région variable de chaîne lourde qui comprend CDR1, CDR2 et CDR3 dans la séquence d'acides aminés de SEQ ID NO : 8, et une région variable de chaîne légère qui comprend CDR1, CDR2 et CDR3 dans la séquence d'acides aminés de SEQ ID NO : 14.
PCT/JP2019/001838 2018-01-23 2019-01-22 Anticorps anti-lck-486 et composition de traitement du cancer comprenant celui-ci WO2019146588A1 (fr)

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WO2001011044A1 (fr) * 1999-08-05 2001-02-15 Kyogo Itoh Antigene de tumeur

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001011044A1 (fr) * 1999-08-05 2001-02-15 Kyogo Itoh Antigene de tumeur

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MATSUEDA, SATOKO ET AL.: "Antitumor activity of antibody against cytotoxic T lymphocyte epitope peptide of lymphocyte - specific protein tyrosine kinase", CANCER SCIENCE, vol. 109, no. 3, 1 February 2018 (2018-02-01), pages 611 - 617, XP055630103, ISSN: 1349-7006 *
MOROI, YOICHI ET AL.: "Accumulation of p601ck in HTLV - I - transformed T Cell Lines Detected by an Anti - Lck Monoclonal Antibody, MOL 171", JAPANESE JOURNAL OF CANCER RESEARCH, vol. 82, no. 8, August 1991 (1991-08-01), pages 909 - 915, XP055630102, ISSN: 0910-5050 *
TAKASHIMA, YASUHIRO: "Vaccine adjuvant that acts directly on the immune system", SMALL ANIMAL CLINIC, vol. 140, June 2005 (2005-06-01), pages 4 - 9 *

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