WO2015082446A1 - Traitement du cancer à l'aide d'un anticorps anti-cdcp1 et d'un taxane - Google Patents

Traitement du cancer à l'aide d'un anticorps anti-cdcp1 et d'un taxane Download PDF

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Publication number
WO2015082446A1
WO2015082446A1 PCT/EP2014/076200 EP2014076200W WO2015082446A1 WO 2015082446 A1 WO2015082446 A1 WO 2015082446A1 EP 2014076200 W EP2014076200 W EP 2014076200W WO 2015082446 A1 WO2015082446 A1 WO 2015082446A1
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Prior art keywords
cancer
antibody
seq
cdcpl
region
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PCT/EP2014/076200
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English (en)
Inventor
Birgit Bossenmaier
Alexander Lifke
Gerhard Niederfellner
Adam NOPORA
Gwendlyn KOLLMORGEN
Oliver KRIETER
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2015082446A1 publication Critical patent/WO2015082446A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to the use of an anti-CDCPl antibody for the treatment of cancer, in combination with a taxane .
  • Human CDCPl (CUB domain containing protein 1, B345, CD318, SIMA135, TRASK; SEQ ID NO : 1 and variants with mutation R525Q (i.e.
  • This protein is found to be
  • carcinoma cells overexpressed in breast, colon and lung cancers. Its expression level is correlated with the metastatic ability of carcinoma cells (Uekita, T. et al . , Am. J. Pathol. 172 (2008) 1729-1739). It has been shown to be tyrosine phosphorylated in a cancer cell line (see WO 2002/004508; Scherl-Mostageer, M. , et al . , Oncogene 20 (2001) 4402-8; Hooper, J., D . , et al . , Oncogene 22 (2003) 1783-94; Perry, S., E., et al FEBS Lett. 581 (2007) 1137-42; Brown, T .
  • WO 2002/004508 refers to CDCPl as tumor associated antigen B345.
  • WO 2004/074481 relates to CDCPl as glycoprotein antigen SIMA135 expressed in metastatic tumor cells.
  • WO 2005/042102 relates to CDCPl as a protein involved in ovarian cancer.
  • WO 2007/005502 relates to methods and compositions for treating diseases targeting CDCPl.
  • WO 2011/023389 relates to humanised antibodies against human CDCPl and the use of these antibodies to treat cancer.
  • WO 2011/023390 relates to antibodies against human CDCPl for the treatment of cancer.
  • Taxanes are diterpenes produced by plants of the genus Taxus (yews) and are widely used as chemotherapy agents (see Hagiwara, H. and Sunada, Y . , Breast Cancer (2004), 11(1), 82-85).
  • the principal mechanism of action of the taxane class of drugs is the disruption of microtubule function, thereby inhibiting the process of cell division.
  • Some toxic side effects associated with taxanes have been reported (see also Hagiwara and Sunada, 2004) .
  • Taxanes were originally derived from natural sources. For example, paclitaxel (Taxol®) was originally derived from the Pacific yew tree (see Rowinsky, E.K. and Donehower, R.C., The New England Journal of
  • paclitaxel may be bound to albumin to form Abraxane®, which is also known as nab-paclitaxel (see Yardley, D.A., J Control Release
  • paclitaxel Another modified form of paclitaxel is Opaxio®, which links paclitaxel to a biodegradable polyglutamate polymer and is also known as paclitaxel poliglumex (see Galic, V.L. et al., Expert Opin Investig Drugs (2011), 20 (6) : 813-821) .
  • Hongdoushans A-C are oxygenated taxane diterpenes, isolated from the wood of Taxus wallichiana.
  • Hongdoushan A C29H44O7
  • hongdoushan B C27H40O7
  • hongdoushan C C27H42O6
  • anti-CDCPl antibodies enhance the efficacy of taxanes to decrease tumour growth. This means that lower doses of taxane can be administered to a patient to achieve the same effect, which reduces that risk of side effects.
  • the invention provides an anti-CDCPl antibody for use in a method of treatment of cancer in a subject, the method comprising administering said antibody and a taxane to the subject.
  • the invention provides a method for the treatment of cancer, wherein the method comprises the step of administering an effective amount of an anti-CDCPl antibody and an effective amount of a taxane to a patient in need thereof.
  • the invention provides the use of an anti-CDCPl antibody in the manufacture of a medicament for the treatment of cancer, wherein the antibody is for administration with a taxane.
  • the invention provides a taxane for use in a method of treatment of cancer in a subject, the method comprising administering a taxane and an anti-CDCPl antibody to the subject.
  • the invention provides the use of a taxane in the manufacture of a medicament for the treatment of cancer, wherein the taxane is for administration with an anti-CDCPl antibody.
  • the invention provides an anti-CDCPl antibody and a taxane for use in combination for the treatment of cancer.
  • the invention provides a method for the treatment of cancer, wherein the method comprises the step of administering an effective amount of an anti-CDCPl antibody in combination with an effective amount of a taxane to a patient in need thereof.
  • the invention provides the use of an anti-CDCPl antibody and a taxane in combination in the manufacture of a medicament for the treatment of cancer.
  • the anti-CDCPl antibody for use in the invention preferably hinds to human CDCP1 ,
  • the anti-CDCPl antibody is a monoclonal antibody.
  • the anti-CDCPl antibody is humanised.
  • the anti-CDCPl antibody binds to essentially the same epitope as the CUB antibody deposited with Deposition No. DSM ACC2551.
  • the anti-CDCPl antibody specifically binds to human CDCP1 with a KD value of less than 1.0 x 10 ⁇ s mol/1, as determined by surface plasmon resonance (BiacoreTM) .
  • the anti-CDCPl antibody is preferably an IgG antibody and more preferably, the anti-CDCPl antibody is of human IgGl subclass.
  • the anti-CDCPl antibody preferably comprises a heavy chain variable domain that comprises an HCDR1 region, an HCDR2 region and an HCDR3 region, wherein the sequences of the HCDR1 region, the HCDR2 region and the HCDR3 region are selected from one of the sets of heavy chain complementary determining sequences (HCDRs) shown in Table 1 below :
  • Table 1 Sequences of preferred sets of HCDRs .
  • the anti-CDCPl antibody preferably comprises a light chain variable domain that comprises an LCDR1 region, an LCDR2 region and an LCDR3 region, wherein the sequences of the LCDRl region, the LCDR2 region and the LCDR3 region are selected from one of the sets of light chain complementary determining sequences (LCDRs) shown in Table 2 below:
  • LCDRs light chain complementary determining sequences
  • Each set of LCDR sequences shown in Table 2 may be combined with any of the sets of HCDR sequences shown in Table 1.
  • the anti-CDCPl antibody comprises (i) a heavy chain variable domain that comprises an HCDR1 sequence shown as SEQ ID NO: 5, an HCDR2 sequence shown as SEQ ID NO: 6 and an HCDR3 sequence shown as SEQ ID NO: 7 [i.e. the hHC4-H set of HCDRs from antibody #135] and a light chain variable domain that comprises an LCDRl sequence shown as SEQ ID NO: 77, an LCDR2 sequence shown as SEQ ID NO: 78 and an LCDR3 sequence shown as SEQ ID NO: 79 [i.e. the hLC-e set of LCDRs from antibody #135] or (ii) a heavy chain variable domain that comprises an HCDRl sequence shown as SEQ ID NO: 5, an HCDR1 sequence shown as SEQ ID NO: 5
  • an HCDR2 sequence shown as SEQ ID NO: 6 and an HCDR3 sequence shown as SEQ ID NO: 7 [i.e. the hHC4-H set of HCDRs from antibody #135]
  • the anti-CDCPl antibody comprises a heavy chain variable domain that comprises an HCDRl sequence shown as SEQ ID NO: 5, an HCDR2 sequence shown as SEQ ID NO: 6 and an HCDR3 sequence shown as SEQ ID NO: 7 [i.e. the hHC4-H set of HCDRs from antibody #135] and a light chain variable domain that comprises an LCDRl sequence shown as SEQ ID NO: 77, an LCDR2 sequence shown as SEQ ID NO:78 and an LCDR3 sequence shown as SEQ ID NO:79 [i.e. the hLC-e set of LCDRs from antibody #135] .
  • the anti-CDCPl antibody comprises a heavy chain variable (VH) domain sequence shown in Table 4:
  • the anti-CDCPl antibody may comprise a heavy chain variable (VH) domain sequence shown in Table 5, or a humanised version thereof.
  • VH heavy chain variable
  • VH domain VH domain sequence SEQ ID NO designation
  • CDCPl-004 VH SGKGLE LAHIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKI
  • CDCPl-012 VH SGKGLEWLAHIYWDDDKRYNPSLKSRLTVSKGTSRNQVLLKI
  • CDCPl-015 VH KGLEWLGVI SGGVTDYNAAFISRLSISKDNSKSQVFFKMNS
  • the anti-CDCPl antibody comprises a light chain variable (VL) domain sequence shown in Table 6: VL domain VL domain sequence SEQ ID NO designation
  • the anti-CDCPl antibody may comprise a light chain variable (VL) domain sequence shown in Table 7, or a humanised version thereof .
  • VL light chain variable
  • the anti-CDCPl antibody comprises one of the
  • the anti-CDCPl antibody comprises (i) the heavy chain variable (VH) sequence shown as SEQ ID NO: 95 (i.e. hHC4-H) and the light chain variable sequence shown as SEQ ID NO: 119 (i.e. hLC-e) or (ii) the heavy chain variable (VH) sequence shown as SEQ ID NO: 95 (i.e. hHC4-H) and the light chain variable sequence shown as SEQ ID NO:lll (i.e. hLC-L2) .
  • the anti-CDCPl antibody comprises the heavy chain variable (VH) sequence shown as SEQ ID NO: 95 (i.e. hHC4-H) and the light chain variable sequence shown as SEQ ID NO:119 (i.e. hLC-e) .
  • the anti-CDCPl antibody may also comprise one of the combinations of a VH and a VL domain shown in Table 9 below, or a humanised version thereof :
  • the taxane for use in the invention is preferably paclitaxel
  • Taxane ⁇ docetaxel
  • Taxotere® docetaxel
  • a modified paclitaxel such as Abraxane® or Opaxio®.
  • the taxane is paclitaxel (Taxol®) .
  • the taxane is docetaxel (Taxotere®) .
  • the anti-CDCPl antibody comprises a heavy chain variable domain that comprises an HCDR1 sequence shown as SEQ ID NO: 5, an HCDR2 sequence shown as SEQ ID NO: 6 and an HCDR3 sequence shown as SEQ ID NO: 7 [i.e. hHC4-H set of HCDRs from antibody #135] and a light chain variable domain that comprises an LCDR1 sequence shown as SEQ ID NO: 77, an LCDR2 sequence shown as SEQ ID NO:78 and an LCDR3 sequence shown as SEQ ID NO:79 [i.e. hLC4-e set of LCDRs from antibody #135], and the taxane is paclitaxel.
  • the anti-CDCPl antibody comprises the heavy chain variable (VH) sequence shown as SEQ ID NO: 95 (i.e. hHC4-H) and the light chain variable sequence shown as SEQ ID NO: 119 (i.e. hLC- e) , and the taxane is paclitaxel.
  • VH heavy chain variable
  • SEQ ID NO: 119 i.e. hLC- e
  • the anti-CDCPl antibody and the taxane are each provided as a pharmaceutical composition, formulated together with a pharmaceutical carrier.
  • the cancer for treatment by the invention may be, for example, lung cancer, non small cell lung (NSCL) cancer, small cell lung cancer (SCL) , bronchioloalviolar cell lung cancer/bronchioloalveolar carcinoma (BAC) , bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, including recurrent ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer
  • carcinoma of the cervix carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, e.g.
  • adult soft tissue sarcoma cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, neoplasms of the central nervous system (CNS) , spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwanomas, ependymonas, medulloblastomas, meningiomas, squamous cell carcinomas, e.g.
  • CNS central nervous system
  • the cancer to be treated comprises a solid tumour. More preferably, the cancer to be treated is lung cancer (such as non small cell lung (NSCL) cancer, small cell lung cancer (SCL) , or bronchioloalviolar cell lung cancer/BAC) , breast cancer (such as metastatic breast cancer (MBC) ) , ovarian cancer (including recurrent ovarian cancer) , gastric cancer
  • lung cancer such as non small cell lung (NSCL) cancer, small cell lung cancer (SCL) , or bronchioloalviolar cell lung cancer/BAC
  • breast cancer such as metastatic breast cancer (MBC)
  • MMC metastatic breast cancer
  • ovarian cancer including recurrent ovarian cancer
  • the cancer to be treated is lung cancer.
  • the cancer to be treated is further characterized by CDCPl expression or overexpression, more preferably by CDCPl expression.
  • the taxane is paclitaxel (Taxol®) and preferred types of cancer to be treated include metastatic breast cancer (MBC) , non small cell lung cancer (NSCLC) (including BAC) , small cell lung cancer (SCLC) , recurrent ovarian cancer and recurrent/metastatic gastric cancer.
  • MBC metastatic breast cancer
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • the taxane is Abraxane® (NabPAC) and the cancer is pancreactic cancer.
  • the anti-CDCPl antibody and Abraxane® may be administered in combination with gemcitabine.
  • the taxane is docetaxel (Taxotere®) and the preferred types of cancer to be treated include MBC,
  • Figure 1 shows the effect of administering paclitaxel in combination with the humanised CUB4 anti-CDCPl antibody #135 (IgGl) with VH and VL domain sequences as shown in Table 8 (and described in WO
  • Figure 2 shows the effect of administering paclitaxel in combination with the humanised CUB4 anti-CDCPl antibody #135 (IgG4) with VH and VL domain sequences as shown in Table 8 (and described in WO
  • the present invention relates to an anti-CDCPl antibody for use in a method of treatment of cancer in a subject, the method comprising administering said antibody and a taxane to the subject, and the inventors demonstrate herein that this combination of agents results in an enhanced reduction of tumour growth, compared to
  • the anti-CDCPl antibody binds to human CDCP1.
  • Human CDCPl ((CUB domain containing protein 1, B345, CD318, SIMA135, TRASK; SEQ ID NO:l and variants with mutation R525Q (i.e.
  • This protein is found to be
  • the anti-CDCPl antibody specifically binds to human
  • binding affinity is of a K D -value of 1.0 x 10 ⁇ 8 mol/1 or lower (e.g. 1.0 x 10 ⁇ 8 mol/1 to 1.0 x 10 ⁇ 13 mol/1) , preferably of a K D -value of 5.0 xl0 ⁇ 9 mol/1 or lower (e.g. 5.0 x 10 "9 mol/1 to 1.0 x 10 "13 mol/1).
  • the binding affinity is determined with a standard binding assay, such as surface plasmon resonance technique (Biacore®) .
  • the anti-CDCPl antibody competes for binding to an epitope on CDCPl with the CUB4 antibody deposited with Deposition No. DSM ACC2551.
  • the anti- CDCPl antibody binds to essentially the same epitope as the CUB4 antibody deposited with Deposition No. DSM ACC2551.
  • the CUB antibody refers to the deposited antibody with the Deposition No. DSM ACC2551 (DSMZ) from DE10242146 (EP 1 396 501, US 7,541,030). Said CUB4 antibody specifically binds to human CDCP1.
  • epitope denotes a protein determinant of human CDCPl capable of specifically binding to an antibody.
  • Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually epitopes have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents .
  • the anti-CDCPl antibody is preferably a monoclonal antibody.
  • the terms "monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of a single amino acid composition.
  • the anti-CDCPl antibody is preferably humanised.
  • the term "being humanised” as used herein denotes an antibody, based on a non-human antibody, e.g. mouse antibody, such as the mouse CUB4 antibody, in which (after chimerization with a human constant region) said VH and VL are humanized by grafting the murine CDRs into the framework region of a human antibody (see e.g. Riechmann, L., et al . , Nature 332 (1988) 323-327; and Neuberger, M . , S., et al . , Nature 314 (1985) 268-270; Queen, C, et al . , Proc. Natl. Acad. Sci. USA 86 (1989)
  • the heavy and light chain variable framework regions can be derived from the same or different human antibody sequences.
  • the human antibody sequences can be the sequences of naturally occurring human antibodies. Human heavy and light chain variable framework regions are listed e.g. in Lefranc, M.P., Current Protocols in Immunology (2000) - Appendix IP A. IP.1-A. IP.37 and are accessible via IMGT, the international ImMunoGeneTics information system®
  • chimeric antibody refers to a monoclonal antibody comprising a variable region, i.e., binding region, from mouse and at least a portion of a constant region derived from a different source or species, usually prepared by recombinant DNA techniques. Chimeric antibodies comprising a mouse variable region and a human constant region are especially preferred. Such mouse/human chimeric antibodies are the product of expressed immunoglobulin genes comprising DNA segments encoding mouse immunoglobulin variable regions and DNA segments encoding human immunoglobulin constant regions. Other forms of "chimeric antibodies" encompassed by the present invention are those in which the class or subclass has been modified or changed from that of the original antibody. Such
  • chimeric antibodies are also referred to as "class-switched antibodies.” Methods for producing chimeric antibodies involve conventional recombinant DNA and gene transfection techniques now well known in the art (see, e.g., Morrison, S., L., et al . , Proc. Natl. Acad Sci . USA 81 (1984) 6851-6855; US 5,202,238 and
  • the anti-CDCPl antibody preferably comprises a heavy chain variable domain that comprises an HCDR1 region, an HCDR2 region and an HCDR3 region, wherein the sequences of the HCDR1 region, the HCDR2 region and the HCDR3 region are selected from one of the sets of heavy chain complementary determining sequences (HCDRs) shown in Table 1 above .
  • HCDRs heavy chain complementary determining sequences
  • the anti-CDCPl antibody preferably comprises a light chain variable domain that comprises an LCDR1 region, an LCDR2 region and an LCDR3 region, wherein the sequences of the LCDR1 region, the LCDR2 region and the LCDR3 region are selected from one of the sets of light chain complementary determining sequences (LCDRs) shown in Table 2 above .
  • LCDRs light chain complementary determining sequences
  • Each set of LCDR sequences shown in Table 2 may be combined with any of the sets of HCDR sequences shown in Table 1.
  • the anti-CDCPl antibody preferably comprises a heavy chain variable (VH) domain sequence shown in Table 4, or a heavy chain variable (VH) domain sequence shown in Table 5 above or a humanised version thereof .
  • the anti-CDCPl antibody comprises a light chain variable (VL) domain sequence shown in Table 6 above, or a light chain variable (VL) domain sequence shown in Table 7 above or a humanised version thereof.
  • VL light chain variable
  • the anti-CDCPl antibody comprises one of the
  • variable domain denotes each of the pair of light and heavy chain domains which are involved directly in binding the antibody to the antigen.
  • the variable light and heavy chain domains have the same general structure and each domain comprises four framework (FR) regions whose sequences are widely conserved, connected by three "hypervariable regions” (or complementary determining regions, CDRs) .
  • the framework regions adopt a ⁇ -sheet conformation and the CDRs may form loops connecting the ⁇ -sheet structure.
  • the CDRs in each chain are held in their three-dimensional structure by the framework regions and form together with the CDRs from the other chain the antigen binding site.
  • the antibody's heavy and light chain CDR3 regions play a particularly important role in the binding specificity/affinity of the antibodies described herein.
  • "Framework" or "FR” regions are those variable domain regions other than the hypervariable region residues as herein defined.
  • the light and heavy chain variable domains of an antibody comprise from N- to C-terminus the domains FR1 , CDRl, FR2, CDR2,
  • CDR and FR regions are determined according to the standard definition of Kabat et al . , Sequences of Proteins of Immunological Interest, 5th ed. , Public Health Service, National Institutes of Health, Bethesda, MD (1991) and/or those residues from a "hypervariable loop".
  • the term "Kabat numbering” or “numbering according to Kabat” or "EU index” unless otherwise stated, is defined as the numbering of the residues in, e.g., an IgG antibody using the EU index as in Kabat et al . (Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).
  • antigen-binding portion of an antibody when used herein refers to the amino acid residues of an antibody which are
  • the antigen-binding portion of an antibody comprises amino acid residues from the "complementary determining regions" or "CDRs".
  • CDRs complementarity determining regions
  • HCDRl denotes the CDRl region of the heavy chain variable region calculated according to Kabat.
  • HCDR2, HCDRH3, LCDR1, LCDR2 and LCDR3 mean the respective regions from the heavy (H) or light (L) chain.
  • amino acid denotes the group of naturally occurring carboxy a-amino acids comprising alanine (three letter code: ala, one letter code: A), arginine (arg, R) , asparagine (asn, N) , aspartic acid (asp, D) , cysteine (cys, C) , glutamine (gin, Q) , glutamic acid (glu, E) , glycine (gly, G) , histidine (his, H) , isoleucine (ile, I), leucine (leu, L) , lysine (lys, K) , methionine (met, M) , phenylalanine (phe, F)
  • the constant region of the anti-CDCPl antibody is preferably of human origin, and is preferably of human IgGl subclass.
  • the constant region includes the heavy chain and light chain constant region of an antibody.
  • the heavy chain constant region comprises in N-terminal to C-terminal direction an antibody constant heavy chain domain 1 (CHI) , an antibody hinge region (HR) , an antibody heavy chain constant domain 2 (CH2) , and an antibody heavy chain constant domain 3 (CH3) , and optionally, in case of an antibody of the subclass IgE, an antibody heavy chain constant domain 4 (CH4) .
  • the light chain constant region comprises an antibody light chain constant domain (CL) .
  • the antibody light chain constant domain (CL) can be ⁇ (kappa) or ⁇ (lambda) .
  • a useful human heavy chain constant region of IgGl subclass comprises an amino acid sequence of SEQ ID NO: 126.
  • a useful human light chain constant region comprises an amino acid sequence of a kappa-light chain constant region of SEQ ID NO: 127; another useful human light chain constant region comprises an amino acid sequence of a lambda-light chain constant region of SEQ ID NO: 128.
  • the "Fc part” of an antibody is not involved directly in binding of an antibody to an antigen, but exhibits various effector functions.
  • An "Fc part of an antibody” is a term well known to the skilled artisan and defined on the basis of papain cleavage of antibodies.
  • antibodies or immunoglobulins are divided in the classes: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes) , e.g. IgGl, IgG2, IgG3, and IgG4, IgAl, and IgA2.
  • the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the Fc part of an antibody is directly involved in ADCC (antibody- dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity) based on complement activation, Clq binding and Fc receptor binding.
  • ADCC antibody- dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • Complement activation is initiated by binding of complement factor Clq to the Fc part of most IgG antibody subclasses. While the influence of an antibody on the complement system is dependent on certain conditions, binding to Clq is caused by defined binding sites in the Fc part. Such binding sites are known in the state of the art and described e.g.
  • binding sites are e.g. L234, L235, D270, N297, E318, K320, K322, P331 and P329 (numbering according to EU index of Rabat, E.A., see below).
  • Antibodies of subclass IgGl, IgG2 and IgG3 usually show complement activation and Clq and C3 binding, whereas IgG4 do not activate the complement system and do not bind Clq and C3.
  • Fc part derived from human origin denotes a Fc part which is either a Fc part of a human antibody of the subclass IgGl, IgG2, IgG3 or IgG4, preferably a Fc part from human IgGl subclass, a mutated Fc part from human IgGl subclass (preferably with a mutation on L234A + L235A) , a Fc part from human IgG4 subclass or a mutated Fc part from human IgG4 subclass (preferably with a mutation on S228P) .
  • human heavy chain constant regions of human IgGl subclass with SEQ ID NO: 126 or 129, of human IgGl subclass with mutations L234A and L235A, of human IgG4 subclass with SEQ ID NO: 130, or of human IgG4 subclass with mutation S228P.
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCC is preferably measured by the treatment of a preparation of CDCPl expressing cells with an antibody according to the invention in the presence of effector cells such as freshly isolated PBMC or purified effector cells from buffy coats, like monocytes or natural killer (NK) cells or a permanently growing NK cell line.
  • effector cells such as freshly isolated PBMC or purified effector cells from buffy coats, like monocytes or natural killer (NK) cells or a permanently growing NK cell line.
  • complement-dependent cytotoxicity denotes a process initiated by binding of complement factor Clq to the Fc part of most IgG antibody subclasses. Binding of Clq to an antibody is caused by defined protein-protein interactions at the so called binding site.
  • Fc part binding sites are known in the state of the art (see above). Such Fc part binding sites are, e.g., characterized by the amino acids L234, L235, D270, N297, E318, K320, K322, P331, and P329 (numbering according to EU index of Kabat) .
  • Antibodies of subclass IgGl, IgG2, and IgG3 usually show complement activation including Clq and C3 binding, whereas IgG4 does not activate the complement system and does not bind Clq and/or C3.
  • oligosaccharide component As described in Umana, P., et al . , Nature Biotechnol. 17 (1999) 176-180, and US 6,602,684.
  • IgGl type antibodies the most commonly used therapeutic antibodies, are glycoproteins that have a conserved N- linked glycosylation site at Asn297 in each CH2 domain.
  • the two complex biantennary oligosaccharides attached to Asn297 are buried between the CH2 domains, forming extensive contacts with the polypeptide backbone, and their presence is essential for the antibody to mediate effector functions such as antibody dependent cellular cytotoxicity (ADCC) (Lifely, M., R.
  • ADCC antibody dependent cellular cytotoxicity
  • GnTIII a glycosyltransferase catalyzing the formation of bisected oligosaccharides, significantly increases the in vitro ADOO activity of antibodies.
  • Alterations in the composition of the Asn297 carbohydrate or its elimination affect also binding to FcyR and Clq (Umana, P., et al . , Nature Biotechnol. 17 (1999) 176-180; Davies, J., et al . , Biotechnol. Bioeng. 74 (2001) 288-294; Mimura, Y-, et al., J. Biol. Chem. 276 (2001) 45539-45547; Radaev, S., et al., J.
  • the anti-CDCPl antibody may be glycosylated (if it comprises an Fc part of IgGl or IgG3 subclass) with a sugar chain at Asn297 whereby the amount of fucose within said sugar chain is 65% or lower
  • the amount of fucose within said sugar chain is between 5% and 65%, preferably between 20% and 40%. In an alternative embodiment, the amount of fucose is 0% of the oligosaccharides of the Fc region at Asn297.
  • “Asn297” according to the invention means amino acid asparagine located at about position 297 in the Fc region. Based on minor sequence variations of antibodies, Asn297 can also be located some amino acids (usually not more than +3 amino acids) upstream or downstream of position 297, i.e. between position 294 and 300.
  • the IgG subclass of the glycosylated antibody may be the human IgGl subclass, or the human IgG3 subclass.
  • the amount of N-glycolylneuraminic acid (NGNA) may be 1% or less and/or the amount of N-terminal alpha-1 , 3-galactose may be 1% or less within said sugar chain.
  • the sugar chains preferably show the characteristics of N-linked glycans attached to Asn297 of an antibody recombinantly expressed in a CHO cell.
  • the sugar chains show characteristics of N-linked glycans attached to Asn297 of an antibody recombinantly expressed in a CHO cell
  • NGNA as used within this application denotes the sugar residue N-glycolylneuraminic acid.
  • Antibodies which are recombinantly expressed in non-glycomodified CHO host cells usually are fucosylated at Asn297 in an amount of at least 85%.
  • the modified oligosaccharides of the antibody may be hybrid or complex.
  • oligosaccharides are hybrid.
  • the bisected, reduced/not-fucosylated oligosaccharides are complex.
  • the "amount of fucose” means the amount of said sugar within the sugar chain at Asn297, related to the sum of all glycostructures attached to Asn297 (e.g. complex, hybrid and high mannose
  • the relative amount of fucose is the percentage of fucose-containing structures related to all glycostructures identified in an N-Glycosidase F treated sample (e.g. complex, hybrid and oligo- and high-mannose structures, resp.) by MALDI-TOF .
  • the anti-CDCPl antibodies for use according to the invention may be generated by any method known in the art (see, for example, WO 2005/042102, WO 2004/074481, WO 2008/133851, WO 2007/005502, WO 2011/023389, WO 2011/023390 and US 2004/0053343) .
  • the anti-CDCPl antibodies are produced by recombinant means .
  • Such methods are widely known in the state of the art and comprise protein expression in prokaryotic and eukaryotic cells with
  • nucleic acids encoding light and heavy chains or fragments thereof are inserted into expression vectors by standard methods. Expression is performed in appropriate prokaryotic or eukaryotic host cells like CHO cells, NS0 cells, SP2/0 cells, HE 293 cells, COS cells, yeast, or E.coli cells, and the antibody is recovered from the cells (supernatant or cells after lysis) .
  • the antibodies may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form. Purification is performed in order to eliminate other cellular components or other contaminants, e.g.
  • HEK 293 A preferred transient expression system (HEK 293) is described by Schlaeger, E.J., and Christensen, K., in Cytotechnology 30 (1999) 71-83 and by Schlaeger, E.J., in J. Immunol. Methods 194 (1996) 191-199.
  • the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to utilize promoters, enhancers and polyadenylation signals.
  • Nucleic acid is "operably linked" when it is placed into a
  • DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • the monoclonal antibodies are suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite
  • DNA and RNA encoding the monoclonal antibodies are readily isolated and sequenced using conventional procedures.
  • the hybridoma cells can serve as a source of such DNA and RNA.
  • the DNA may be inserted into expression vectors, which are then transfected into host cells such as HEK 293 cells, CHO cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of recombinant monoclonal
  • the expressions "cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include progeny.
  • the words “transformants” and “transformed cells” include the primary subject cell and cultures derived therefrom without regard for the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. Where distinct
  • transformation refers to process of transfer of a vectors/nucleic acid into a host cell. If cells without daunting cell wall barriers are used as host cells, transfection is carried out e.g. by the calcium phosphate
  • transcripts and the encoded polypeptides are collectively referred to as gene product. If the polynucleotide is derived from genomic DNA, expression in a eukaryotic cell may include splicing of the mRNA.
  • a "vector” is a nucleic acid molecule, in particular self- replicating, which transfers an inserted nucleic acid molecule into and/or between host cells.
  • the term includes vectors that function primarily for insertion of DNA or RNA into a cell (e.g., chromosomal integration) , replication of vectors that function primarily for the replication of DNA or RNA, and expression vectors that function for transcription and/or translation of the DNA or RNA. Also included are vectors that provide more than one of the functions as
  • an "expression vector” is a polynucleotide which, when introduced into an appropriate host cell, can be transcribed and translated into a polypeptide.
  • An “expression system” usually refers to a suitable host cell comprised of an expression vector that can function to yield a desired expression product.
  • the taxane for use in the invention may be any member of the taxane (i.e. diterpene) class of drugs. These include those obtained from natural sources (such as paclitaxel; Taxol®) , those that have been synthetically produced (such as docetaxel; Taxotere®) , as well as modified taxanes (such as Abraxane® and Opaxio®) .
  • the anti-CDCPl antibody and the taxane are each provided as a pharmaceutical composition, formulated together with a pharmaceutical carrier.
  • pharmaceutical carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and. absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g. by injection or infusion).
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • chlorobutanol phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the anti-CDCPl antibody and the taxane may be used to treat any type of cancer.
  • types of cancer suitable for treatment by the invention include lung cancer, non small cell lung (NSCL) cancer, small cell lung cancer (SCL) , bronchioloalviolar cell lung cancer/bronchioloalveolar carcinoma (BAC) , bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, including recurrent ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer (including recurrent and metastatic gastric cancer) , colon cancer, breast cancer (including metastatic breast cancer (MBC) ) , uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin ' s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endoc
  • adult soft tissue sarcoma cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, neoplasms of the central nervous system (CNS) , spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas,
  • CNS central nervous system
  • schwanomas ependymonas, medulloblastomas , meningiomas, squamous cell carcinomas, e.g. squamous cell carcinoma of the head and neck
  • the cancer to be treated comprises a solid tumour. More preferably, the cancer to be treated is lung cancer (such as non small cell lung
  • the cancer to be treated is lung cancer.
  • the cancer to be treated is further characterized by CDCP1 expression or
  • overexpression more preferably by CDCP1 expression.
  • the subject to be treated is preferably a human patient.
  • the anti-CDCPl antibody or the taxane may be administered to a subject by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. To administer a compound by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation .
  • the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Pharmaceutical carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art.
  • the anti-CDCPl antibody and the taxane are preferably administered parenterally.
  • parenteral administration and
  • administration other than enteral and topical administration usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial , intrathecal, intracapsular,
  • intraorbital intracardiac, intradermal, intraperitoneal
  • transtracheal subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • the compounds the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present
  • compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient, i.e. "an effective amount".
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in
  • compositions employed the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts .
  • the composition must be sterile and fluid to the extent that the composition is deliverable by syringe.
  • the carrier preferably is an isotonic buffered saline solution. Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition.
  • the anti-CDCPl antibody and the taxane may be administered to the subject simultaneously, separately or sequentially, i.e. the anti- CDCPl antibody and the taxane may be administered at the same time or at different times.
  • the anti-CDCPl antibody and the taxane may be administered to the subject as a co-formulation (i.e. the anti- CDCPl antibody and the taxane are present in the same composition) or as a separate composition.
  • the anti-CDCPl antibody and the taxane may be administered at different dosing frequenices and/or
  • the anti-CDCPl antibody and the taxane may be any anti-CDCPl antibody and the taxane.
  • the anti-CDCPl antibody and the taxane are preferably administered within one week, two weeks, three weeks, four weeks, five weeks or six weeks of each other.
  • Use of an anti-CDCPl antibody and a taxane in combination includes simultaneous, separate or sequential administration of anti-CDCPl antibody, i.e. the anti-CDCPl antibody and the taxane may be administered at the same time or at different times.
  • Use of an anti-CDCPl antibody and a taxane in combination encompasses administration of the antibody and the taxane as a co-formulation (i.e. the anti-CDCPl antibody and the taxane are present in the same composition) and/or administration as separate compositions.
  • SEQ ID NO: 128 lambda constant light chain region from human origin
  • Immunodeficient SCID/bg mice were purchased from Charles River (Sulzfeld, Germany) . Animals used in experiments were between 8 and 16 weeks of age. All experiments were conducted in accordance with local governmental regulations and Roche internal guidelines.
  • Tumour cells having in vitro passage number 4-5 were used for inoculation. 4 x 10 6 for QG-56 tumour cells and 5 x 10 6 for H322M tumour cells, respectively, were injected subcutaneously into the right flank of mice. 10 mice were used in each group and Figures 1 and 2 show the median results from each of these groups.
  • QG-56 tumour cells are human non small cell lung carcinoma (squamous) cells from a Japanese patient and H322M tumour cells are non small cell lung cancer cells obtained from the NCI collection.
  • humanized CUB4 anti-CDCPl antibody No. 135 (described in WO2011/023389) was administered intraperitoneally in once-weekly intervals at 10 mg/kg alone or in combination with Paclitaxel.
  • This antibody has the VH and VL domain sequences shown as SEQ ID NOs : 95 and 119 respectively.
  • the IgGl subclass of this antibody was used, while in the H322M studies, the IgG4 subclass was used.
  • Paclitaxel was given
  • Control animals received vehicle (20mM Histidine, 150mM NaCl, 0.01% Tween 80) .
  • Table 10 Inhibition of tumour growth by an anti-CDCPl antibody and/or paclitaxel.
  • the results in Figure 2 obtained using an antibody of the human IgG4 subclass show that the anti-CDCPl antibody increases the efficacy of paclitaxel irrespective of whether the Fc region is IgGl or IgG4. This indicates that inhibition of CDCPl signalling underlies the increased efficacy of the combination treatment independently of potential effector function.

Abstract

La présente invention concerne l'utilisation d'un anticorps anti-CDCP1 pour le traitement du cancer, en combinaison avec un taxane. L'invention concerne également des méthodes de traitement du cancer à l'aide d'un anticorps anti-CDCP1 et d'un taxane.
PCT/EP2014/076200 2013-12-02 2014-12-02 Traitement du cancer à l'aide d'un anticorps anti-cdcp1 et d'un taxane WO2015082446A1 (fr)

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WO2019084319A1 (fr) * 2017-10-25 2019-05-02 The Regents Of The University Of California Anticorps contre cdcp1 pour le traitement et la détection du cancer
CN110234348A (zh) * 2016-12-16 2019-09-13 蓝鳍生物医药公司 抗-含cub结构域蛋白1(cdcp1)抗体、抗体药物缀合物及其使用方法
WO2020157334A1 (fr) 2019-02-01 2020-08-06 Fondazione Per L'istituto Oncologico Di Ricerca (Ior) Procédés de traitement du cancer de la prostate résistant à la castration
WO2023246701A1 (fr) * 2022-06-20 2023-12-28 四川汇宇制药股份有限公司 Anticorps et son utilisation

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