WO2023007374A1 - Method of treatment of cancer pain with tanezumab - Google Patents

Method of treatment of cancer pain with tanezumab Download PDF

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Publication number
WO2023007374A1
WO2023007374A1 PCT/IB2022/056903 IB2022056903W WO2023007374A1 WO 2023007374 A1 WO2023007374 A1 WO 2023007374A1 IB 2022056903 W IB2022056903 W IB 2022056903W WO 2023007374 A1 WO2023007374 A1 WO 2023007374A1
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pain
cancer
patient
tanezumab
treatment
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PCT/IB2022/056903
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French (fr)
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Alex Osei AGYEMANG
Warren BAO
Mark Thomas BROWN
Christine Ruth WEST
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Pfizer Inc.
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Publication of WO2023007374A1 publication Critical patent/WO2023007374A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present invention relates to the treatment of cancer pain with tanezumab, an anti-nerve growth factor (NGF) antibody.
  • NGF anti-nerve growth factor
  • the skeleton is the third most common target of metastatic cancer and can be one of the earliest sites affected (Schulman KL, Kohle J. Cancer 2007; 109(11):2334-42).
  • Cancers of the breast and prostate are particularly likely to spread to bone; about 70% of patients who die from these diseases have evidence of skeletal involvement at autopsy.
  • Carcinomas of the thyroid, kidney, and bronchus also often cause bone metastasis with a post-mortem incidence of 30% to 40%, but, by contrast, tumors of the gastrointestinal tract do so rarely, affecting only about 5% of patients dying from these malignancies. Given the high prevalence of carcinomas of the breast, prostate, and lung, it is estimated that these cancers probably account for more than 80% of cases of metastatic bone disease (Rubens RD. European Journal of Cancer 1998; 34(2):210- 13).
  • metastatic bone cancer is a chronic condition, with survival from the time of diagnosis varying significantly among the various tumor types.
  • median survival time from diagnosis is measurable in years.
  • advanced lung cancer it is usually measured in months (Upton A, Berenson JR, Body JJ, et al. Clin Cancer Res 2006; 12(20 Suppl) 6209s- 12s).
  • Pain associated with cancer is a substantial problem that negatively impacts patients’ quality of life, especially as emerging therapies directed against the underlying cancer have begun to prolong patient survival. While pain can result from a number of causes, bone metastasis is the most common cause of cancer pain, occurring in 60 to 84% of patients (Langford DJ, Tripathy D, Paul SM, et al. Journal of Pain 2011 ; 12(4):495-507; Mercadante S. Pain 1997; 69:1-18). More than 70% of patients with bone metastasis report moderate to severe pain that has a significant impact on their functional status and quality of life (Langford DJ, Tripathy D, Paul SM, et al. Journal of Pain 2011 ; Yau V, Chow E, Davis L, et al. J Pain Symptom Management 2004; 27(1 ):1 -3. 17; Rustoen T, Mourn T, Padilla G, et al. J Pain Symptom Management 2005 30(3):234-42).
  • Treatment of bone metastasis is primarily palliative, in order to relieve pain, prevent development of pathological fractures and improve mobility and function (Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011 ; 16(3)441-58; Houston SJ, Rubens RD. Clin Orthop Relat Res 1995; 312:539-42).
  • Conventional treatment uses a multidisciplinary approach including local radiotherapy to the painful area along with systemic treatment (hormone therapy or chemotherapy or radioisotopes) and supportive care such as analgesic therapy, corticosteroids and bisphosphonates (Mercadante F, Fulfaro F. Curr Opin Oncol 2007; 19:308-14. 21 ; Goldberg G, Morrison R.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 inhibitors could affect bone health by inhibiting COX enzymes which reduce synthesis of prostaglandins (Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011; 16(3)441-58).
  • opioids may impair bone metabolism and chronic opioid users have an increased risk of fractures (Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011 ; 16(3)441-58; Buckeridge D, Fluang A, Hanley J, et al. J Am Geriatr Soc 2010; 58:1664-70).
  • opioids may have a possible role in tumor progression (Lennon FE, Moss J, Singleton PA. Anesthesiology 2012; 116(4):940-45).
  • Pain 1995; 63:65-76 suggested that 76% of patients could achieve good pain relief using the principles of the ladder, a further 12% achieved satisfactory efficacy and 12% had inadequate efficacy. Unfortunately, subsequent studies suggest that these results are not achieved in clinical practice and that much cancer pain continues to be poorly controlled (Forbes K. Clinical Oncology 2011 ; 23:379-80).
  • Tanezumab is an anti-NGF antibody that binds to and inhibits the actions of nerve growth factor (NGF).
  • the Nerve Growth Factor Inhibitor (NGFI) class may offer an important breakthrough in the treatment of chronic pain and has undergone clinical investigation for the treatment of pain associated with osteoarthritis or other chronic pain conditions.
  • the invention disclosed herein is directed to treatment of cancer pain predominantly due to bone metastases in patients receiving background opioid therapy.
  • the invention provides a method of treating cancer pain in a patient in need thereof, the method comprising administering 20 mg of tanezumab subcutaneously to the patient, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis, cancer originated in bone, or multiple myeloma, and wherein the patient has had inadequate pain relief with opioid analgesics.
  • the patient has: i. an average Pain Score of at least 5 for the index cancer pain site; ii. a Patient's Global Assessment of Cancer Pain of "fair”, “poor” or “very poor”; iii. an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1, or 2; and iv. no joint safety event selected from: 1) rapidly progressive osteoarthritis (type 1 or type 2), 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fracture, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
  • ECOG Eastern Cooperative Oncology Group
  • Clinical benefit of the treatment according to the invention effectively reduces pain at the index cancer pain site.
  • tanezumab is administered every eight weeks. In some embodiments, tanezumab is administered for at least two or more doses at eight weekly intervals. In some embodiments, tanezumab is administered to the patient for at least 8, 16, 24, 32, 40 or 48 weeks.
  • the treatment effectively reduces average pain intensity at the index cancer pain site; effectively reduces worst pain intensity at the index cancer pain site; and/or effectively reduces patient global assessment of cancer pain at the index cancer pain site.
  • the treatment effectively reduces pain at the index cancer pain site at at least 1, 2, 3, 4, 5, 6, 7, or 8 week(s) after start of treatment. In some embodiments, the treatment effectively reduces pain at the index cancer pain site at weeks 2, 4, and 6, in addition to week 8 after start of treatment. In some embodiments, the treatment effectively reduces pain at the index cancer pain site at at least 16, 24, 32, 40, 48 or 56 weeks after start of treatment.
  • the treatment effectively improves pain at the index cancer pain site compared to a baseline value prior to or at start of treatment.
  • the patient requires background opioid therapy and/or may require opioid medication.
  • the patient may require daily opioid medication.
  • the treatment results in reduced opioid use which may be reduced average opioid consumption, and in some embodiments reduced average daily opioid consumption.
  • the treatment improves cancer pain measures compared to treatment with an opioid analgesic.
  • the treatment improves cancer pain measures compared to treatment with morphine.
  • the treatment effectively improves the cancer pain for at least 24 weeks, 32 weeks, 40 weeks, 48 weeks, or 56 weeks after start of treatment.
  • the treatment provides 10%, 15%, 20%, 25%, 30%, 35% of patients with at least 30%, 50%, 70% or 90% improvement in cancer pain. In some embodiments, the treatment provides at least 20% of patients with at least 50% improvement in cancer pain at week 8 after start of treatment.
  • the patient has a history of inadequate pain relief from or intolerance to prior therapy including analgesic therapy.
  • the prior therapy can comprise at least agents used for treatment of cancer pain. These agents can include acetaminophen/low-dose NSAIDs; prescription NSAIDs; opioids; tapentadol; tricyclic antidepressants; benzodiazepines or skeletal muscle relaxants; lidocaine patch; and/or duloxetine or other serotonin-norepinephrine reuptake inhibitors.
  • the patient was previously treated with the analgesic therapy prior to administering tanezumab. In some embodiments the patient continues to receive analgesic therapy during treatment with tanezumab.
  • the analgesic therapy may be the same as the analgesic therapy prior to administering tanezumab.
  • the patient has a history of treatment with at least one, at least two, at least three, at least four or at least five prior therapies.
  • the prior therapies may be from the same or different class of agent for treatment of cancer pain.
  • the patient experiences some benefit from the analgesic therapy, but still requires additional pain relief.
  • cancer pain may be determined by an average pain score of at least 5 for the index cancer pain site; a baseline Patient’s Global Assessment of cancer pain of “fair”, “poor” or “very poor”; or an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
  • the analgesic therapy comprises the administration of an opioid to the patient. In some embodiments the analgesic therapy comprises the administration of morphine to the patient.
  • the treatment averts opioid addiction in the patient. In some embodiments, the treatment avoids administration of an opioid and averts opioid addiction.
  • the patient has a history of addiction to analgesics. In some embodiments, the patient has a history of addiction to opioids. In some embodiments, the patient has a history of addiction to morphine or tramadol.
  • the analgesic may be selected from opioids, NSAIDs, acetaminophen.
  • the NSAID is selected from ibuprofen, naproxen, naprosyn, diclofenac, ketoprofen, tolmetin, slindac, mefenamic acid, meclofenamic acid, diflunisal, flufenisal, piroxim, sudoxicam, isoxicam; a COX-2 inhibitor selected from celecoxib, rofecoxib, DUP-697, flosulide, meloxicam, 6-methoxy-2 naphthylacetic acid, MK-966, nabumetone, nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.
  • the opioid may be any compound exhibiting morphine like biological activity.
  • the opioid analgesic is selected from: tramadol, morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or combinations thereof.
  • the patient is not administered an NSAID during the treatment with tanezumab. In some embodiments, the patient is not administered concomitant NSAID during the treatment with tanezumab. In some embodiments the patient is not administered an NSAID for any more than 10 days in an eight-week treatment interval. In some embodiments, the patient is not administered an NSAID for 16 weeks after the last dose of tanezumab.
  • the patient is not administered a placebo which may be an oral placebo.
  • the patient has moderate to severe cancer pain which may be predominantly due to bone metastasis.
  • the patient has an average pain score of greater than 5 at the index cancer site. In some embodiments, the patient has an average pain score of about 6 at the index cancer pain site. In some embodiments, the patient has an average pain score of about 7 at the index cancer pain site.
  • the patient has an average pain score of greater than 5 at the index cancer pain site and/or has a total weekly opioid use of less than 150, 125, 100, or 75 morphine equivalents. In some embodiments, the patient has a total weekly opioid use of less than or equal to 100 morphine equivalents. In some embodiments, the patient has a total weekly opioid use of less than or equal to 99, 98, 97, 96, 95 mg of morphine equivalence. In some embodiments, the patient has a total weekly opioid use of less than or equal to 70, 65, 60, 55 or 50 morphine equivalents. In some embodiments, the patient has a total weekly opioid use of less than or equal to 60.5 morphine equivalents.
  • the patient has had cancer pain for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 or at least 12 months prior to treatment with tanezumab. In one embodiment, the patient has had cancer pain for at least 3 months. In some embodiments, the patent has had cancer pain for at least 18, 24, 30, 36, 42, 48 or 56 months prior to treatment with tanezumab.
  • the cancer pain is from cancer originated in bone. In some embodiments, the cancer pain is from osteosarcoma. In some embodiments, the cancer pain is from cancer metastasized to bone (i.e., bone metastasis). In some embodiments, the bone metastasis is prostate cancer metastasized to bone. In some embodiments, the bone metastasis is breast cancer metastasized to bone. In some embodiments, the bone metastasis is lung cancer metastasized to bone. In some embodiments, the bone metastasis is sarcoma metastasized to bone. In some embodiments, the bone metastasis is kidney cancer metastasized to bone. In some embodiments, the bone metastasis is multiple myeloma metastasized to bone.
  • the cancer pain is from cancer other than breast cancer, prostate cancer or lung cancer metastasized to bone.
  • the tumor is less aggressive as assessed by ECOG Performance Status Score prior to or at start of treatment.
  • the ECOG Performance Status Score is less than or equal to 1 prior to or at start of treatment.
  • the patient does not receive concomitant anti-cancer therapy.
  • tanezumab is administered for at least two, three, four, five, six or more doses at eight weekly intervals. In some embodiments, tanezumab is administered to the patient for at least 16, 24, 32, 40, 48, 56, 56, 72, 80, 88 or 96 weeks. In some embodiments, tanezumab is administered to the patient for at least 16 weeks. In some embodiments tanezumab is administered to the patient for at least 24 weeks. In some embodiments tanezumab is administered to the patient for at least 48 weeks.
  • the patient prior to treatment with tanezumab does not have osteoarthritis and/or pain associated with osteoarthritis.
  • the patient prior to treatment with tanezumab has no or possible radiographic evidence of hip osteoarthritis (Kellgren Lawrence Grade ⁇ 1) and/or does not meet the American College of Rheumatology (ACR) clinical and radiographic criteria; and/or does not have pain associated with hip osteoarthritis.
  • ACR American College of Rheumatology
  • the patient prior to treating with tanezumab has no symptoms and radiographic evidence of osteoarthritis of the shoulder.
  • the patient is subjected to radiographic assessment of the knee, hip and/or shoulder prior to starting treatment with tanezumab. In some embodiments, if radiographic assessment identified rapidly progressive osteoarthritis of the joint, the patient is excluded from the treatment.
  • the method further comprises conducting a radiographic assessment of the knee, hip and/or shoulder at regular intervals during treatment.
  • a patient may be excluded from treatment, before or during treatment, if the patient has been diagnosed as having osteoarthritis of the knee or hip as defined by the American College of Rheumatology (ACR) clinical and radiographic criteria; having Kellgren-Lawrence Grade >2 radiographic evidence of hip osteoarthritis; and/or having Kellgren-Lawrence Grade >3 radiographic assessment of knee osteoarthritis and/or having symptoms and radiographic evidence of osteoarthritis of the shoulder.
  • ACR American College of Rheumatology
  • a patient may be excluded from treatment, before or during treatment, if there is radiographic evidence of any of the following conditions as determined by the central radiology reviewer and as defined in an imaging atlas at screening: 1) rapidly progressive osteoarthritis, 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
  • SPONK spontaneous osteonecrosis of the knee
  • a patient may be excluded from treatment, before or during treatment, if there is radiographic evidence of any of the following conditions in any screening radiograph as determined by a central radiology reviewer and as defined in an imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; other arthropathies (e.g., rheumatoid arthritis), systemic metabolic bone disease (e.g., pseudogout, Paget’s disease; metastatic calcifications), large cystic lesions, stress or traumatic fracture.
  • excessive malalignment of the knee severe chondrocalcinosis
  • other arthropathies e.g., rheumatoid arthritis
  • systemic metabolic bone disease e.g., pseudogout, Paget’s disease
  • metastatic calcifications e.g., metastatic calcifications
  • patients not having satisfactory clinical response after receiving two doses do not receive further doses.
  • the method further comprises administering an effective amount of a second therapeutic agent.
  • tanezumab may be administered in conjunction with other therapies for bone cancer, such as radiation, and chemotherapy. Tanezumab may also be administered in conjunction with other analgesics used for cancer pain. The amount of these analgesics administered for cancer pain alleviation may be reduced, comparing to the amount administered in the absence of tanezumab. Adverse effects due to these analgesics may be reduced or eliminated when they are co-administered with tanezumab.
  • the patient prior to treatment with tanezumab, has one or more of a) cancer pain from cancer other than from breast cancer, prostate cancer or lung cancer metastasized to bone; b) an average pain score of about 6 at the index cancer pain site; c) a total weekly median opioid use of less than about 100 morphine equivalents; d) a tumor that is less aggressive as assessed by ECOG Performance Status Score; and e) no concomitant anti-cancer therapy.
  • the patient has two or more, three or more, four or more, or all of these characteristics.
  • the patient has a tumor that is less aggressive having a ECOG Performance Status Score of less than or equal to 1. In some embodiments, the patient does not have a tumor having a ECOG Performance Status Score of 2 or more. An ECOG Performance Status Score of 2 or more is indiciative of a more aggressive tumor.
  • tanezumab for use in a method of treating cancer pain as described herein. Also provided is the use of tanezumab in the manufacture of a medicament for use in a method for treating cancer pain as described herein.
  • such embodiments are also further embodiments of tanezumab for use in that treatment, or alternatively of the use of tanezumab in the manufacture of a medicament for use in that treatment.
  • Figure 1 is a study outline for the study described in Example 1.
  • Figure 2 shows the change from baseline for daily average pain intensity at the index cancer pain site up to week 8.
  • Figure 3 shows the change from baseline for daily average pain intensity at the index cancer pain site up to week 24.
  • Figure 4 shows the change in average daily pain intensity at the index cancer pain site up to week 8.
  • Figure 5 shows the change from baseline for daily average pain intensity at the index cancer pain site up to day 7.
  • Figure 6 shows response rates for daily average pain intensity at index cancer pain site at week 8.
  • Figure 7 shows >50% response rates over time in daily average pain intensity at index cancer pain site.
  • Figure 8 shows change from baseline for daily worst pain intensity at the index cancer pain site up to week 24.
  • Figure 9 shows average daily pain at index cancer pain site change from baseline to week 8 by primary cancer.
  • Figure 10 shows average daily pain at index cancer pain site change from baseline to week 8 by geographical region.
  • Figure 11 shows average daily pain at index cancer pain site change from baseline to week 8 by median pain score at baseline (score of 6).
  • Figure 12 shows average daily pain at index cancer pain site change from baseline to week 8 by median opioid use at baseline (96 mg morphine equivalence).
  • Figure 13 shows average daily pain at index cancer pain site change from baseline to week 8 by tumor aggressiveness.
  • Figure 14 shows average daily pain at index cancer pain site change from baseline to week 8 by concomitant anticancer therapy.
  • the invention disclosed herein is directed to treatment of cancer pain predominantly due to bone metastases in patients receiving background opioid therapy.
  • the invention provides a method of treating cancer pain in a patient in need thereof, the method comprising administering 20 mg of tanezumab subcutaneously to the patient, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis, cancer originated in bone, or multiple myeloma, and wherein the patient has had inadequate pain relief with opioid analgesics.
  • the patient has: i. an average Pain Score of at least 5 for the index cancer pain site; ii. a Patient's Global Assessment of Cancer Pain of "fair”, “poor” or “very poor”; iii. an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1, or 2; and iv. no joint safety event selected from: 1) rapidly progressive osteoarthritis (type 1 or type 2), 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fracture, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
  • ECOG Eastern Cooperative Oncology Group
  • an “antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc.
  • the term encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.
  • Antigen binding portions include, for example, Fab, Fab’, F(ab , Fd, Fv, domain antibodies (dAbs, e.g., shark and camelid antibodies), fragments including complementarity determining regions (CDRs), single chain variable fragment antibodies (scFv), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide.
  • An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class.
  • immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, lgG3, lgG4, IgAi and lgA2.
  • the heavy- chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • variable region of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination.
  • variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity determining regions (CDRs) also known as hypervariable regions, and contribute to the formation of the antigen binding site of antibodies.
  • FRs framework regions
  • CDRs complementarity determining regions
  • variants of a subject variable region are desired, particularly with substitution in amino acid residues outside of a CDR region (i.e., in the framework region), appropriate amino acid substitution, preferably, conservative amino acid substitution, can be identified by comparing the subject variable region to the variable regions of other antibodies which contain CDR1 and CDR2 sequences in the same canonical class as the subject variable region (Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987).
  • definitive delineation of a CDR and identification of residues comprising the binding site of an antibody is accomplished by solving the structure of the antibody and/or solving the structure of the antibody-ligand complex. In certain embodiments, that can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, and the conformational definition.
  • the Kabat definition is a standard for numbering the residues in an antibody and is typically used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8.
  • the Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account positions of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83.
  • the AbM definition uses an integrated suite of computer programs produced by Oxford Molecular Group that model antibody structure.
  • the AbM definition models the tertiary structure of an antibody from primary sequence using a combination of knowledge databases and ab initio methods, such as those described by Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198.
  • the contact definition is based on an analysis of the available complex crystal structures.
  • CDRs In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues do not significantly impact antigen binding.
  • a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches.
  • the methods used herein may utilize CDRs defined according to any of these approaches.
  • the CDRs may be defined in accordance with any of Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.
  • a “constant region” of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or may be made by recombinant DNA methods such as described in U.S. Pat. No. 4,816,567.
  • the monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCaffertyetal., 1990, Nature 348:552-554, for example.
  • humanized antibody refers to forms of non-human (e.g. murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity.
  • the humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance.
  • Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • the humanized antibody may include residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance.
  • the humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will include at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.
  • the antibodies have Fc regions modified as described in PCT International Publication No. WO 99/58572.
  • Other forms of humanized antibodies have one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H 1 , CDR H2, or CDR H3) which may be altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody.
  • humanized antibodies may include residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance (e.g., to obtain desired affinity).
  • the humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will include at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Such “humanized” antibodies may include antibodies wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some framework residues are substituted by residues from analogous sites in rodent antibodies.
  • a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen binding residues.
  • chimeric antibody is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • Tanezumab is a humanized immunoglobulin G Type 2 (lgG2) monoclonal antibody directed against human nerve growth factor (NGF). Tanezumab binds to human NGF with high affinity and specificity, and blocks the activity of NGF effectively in cell culture models. Tanezumab and/or its murine precursor have been shown to be an effective analgesic in animal models of pathological pain including arthritis, cancer pain, and post-surgical pain. Tanezumab has the sequences for the variable heavy chain region and variable light chain region of SEQ ID NOs: 1 and 2, respectively. The heavy chain and light chain sequences are provided in SEQ ID NO: 9 and 10, or SEQ ID NOs: 11 and 10.
  • the C-terminal lysine (K) of the heavy chain amino acid sequence of SEQ ID NO: 9 is optional and may be processed, resulting in a heavy chain amino acid sequence lacking the C-terminal lysine (K) and having the sequence shown in SEQ ID NO: 11. Sequences of tanezumab are provided in Table 1 below. Tanezumab is described, as antibody E3, in W02004058184, herein incorporated by reference.
  • polynucleotide or “nucleic acid,” as used interchangeably herein, refer to chains of nucleotides of any length, and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the chain.
  • the sequence of nucleotides may be interrupted by non-nucleotide components.
  • a polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • Other types of modifications include, for example, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L- lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g.,
  • any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports.
  • the 5’ and 3’ terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms.
  • Other hydroxyls may also be derivatized to standard protecting groups.
  • Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2’-0-methyl-, 2’-0-allyl, 2’-fluoro- or 2’-azido-ribose, carbocyclic sugar analogs, alpha- or beta-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside.
  • One or more phosphodiester linkages may be replaced by alternative linking groups.
  • linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(0)S(“thioate”), P(S)S (“dithioate”), (0)NR 2 (“amidate”), P(0)R, P(0)OR’, CO or CH2 (“formacetal”), in which each R or R’ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.
  • An antibody that “preferentially binds” or “specifically binds” (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art.
  • a molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances.
  • an antibody that specifically or preferentially binds to a target (e.g., PD-1) epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other target epitopes or non-target epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target mayor may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.
  • substantially pure refers to material which is at least 50% pure (i.e., free from contaminants), more preferably, at least 90% pure, more preferably, at least 95% pure, yet more preferably, at least 98% pure, and most preferably, at least 99% pure.
  • a “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts.
  • Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation.
  • a host cell includes cells transfected in vivo with a polynucleotide(s) of this invention.
  • the term "Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain.
  • the "Fc region” may be a native sequence Fc region or a variant Fc region.
  • the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
  • the numbering of the residues in the Fc region is that of the EU index as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.
  • the Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3. As is known in the art, an Fc region can be present in dimer or monomeric form.
  • Fc receptor and “FcR” describe a receptor that binds to the Fc region of an antibody.
  • the preferred FcR is a native sequence human FcR.
  • a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
  • FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • FcRs are reviewed in Ravetch and Kinet, 1991, Ann. Rev. Immunol., 9:457-92; Capel et al., 1994, Immunomethods, 4:25-34; and de Flaas et al., 1995, J. Lab. Clin. Med., 126:330-41.
  • FcR also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyeret al., 1976, J. Immunol., 117:587; and Kim et al., 1994, J. Immunol., 24:249).
  • the term “compete”, as used herein with regard to an antibody means that a first antibody, or an antigen-binding portion thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or an antigen-binding portion thereof, such that the result of binding of the first antibody with its cognate epitope is detectably decreased in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody.
  • the alternative, where the binding of the second antibody to its epitope is also detectably decreased in the presence of the first antibody can, but need not be the case. That is, a first antibody can inhibit the binding of a second antibody to its epitope without that second antibody inhibiting the binding of the first antibody to its respective epitope.
  • each antibody detectably inhibits the binding of the other antibody with its cognate epitope or ligand, whether to the same, greater, or lesser extent, the antibodies are said to “cross-corn pete” with each other for binding of their respective epitope(s).
  • Both competing and cross- competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate, based upon the teachings provided herein, that such competing and/or cross-competing antibodies are encompassed and can be useful for the methods disclosed herein.
  • a “functional Fc region” possesses at least one effector function of a native sequence Fc region.
  • exemplary “effector functions” include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity; phagocytosis; down-regulation of cell surface receptors (e.g. B cell receptor), etc.
  • Such effectorfunctions generally require the Fc region to be combined with a binding domain (e.g. an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions.
  • a “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature.
  • a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effectorfunction of the native sequence Fc region.
  • the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide.
  • the variant Fc region herein will preferably possess at least about 80% sequence identity with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably, at least about 90% sequence identity therewith, more preferably, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity therewith.
  • treatment is an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include reduction or improvement in cancer pain, for example as compared to before administration of tanezumab.
  • “Ameliorating” means a lessening or improvement of cancer pain, for example as compared to not administering tanezumab as described herein. “Ameliorating” also includes shortening or reduction in duration of a symptom.
  • an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired results.
  • an effective amount prevents, alleviates or ameliorates cancer pain.
  • beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as reducing cancer pain, decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, and/or delaying the progression of the disease in patients.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • the term “inadequate treatment response to prior therapy” refers to a patient who has experienced an adverse event after treatment with the prior therapy; who is refractory to treatment with the prior therapy; who shows no clinically meaningful improvement in one or more measures of cancer pain with prior therapy; who experiences some benefit from prior therapy but still requires additional pain relief; who is addicted to the prior therapy (including analgesics such as opioids); and/or who is unwilling to take the prior therapy.
  • the patient has a history of inadequate pain relief from or intolerance to prior therapy, which may comprise at least three different classes of analgesics.
  • the difference between the clinical measure at baseline and during/after treatment is compared and used to determine whether the cancer pain has improved, and the treatment is effective.
  • This comparison can include comparison to placebo or to one or more of the prior therapies.
  • the comparison can be to placebo or to treatment with an opioid analgesic, such as morphine or tramadol; or a NSAID, such as celecoxib.
  • the clinical measure can be average daily pain intensity.
  • the average daily pain intensity measure can be determined for the patient at baseline and then determined throughout the treatment period, such as at weeks 2, 4, 6, 8, 16, 24, 32, 40, 48, 56, or longer.
  • the worst daily pain intensity can also be determined in this manner.
  • the Patient Global Assessment (PGA) of cancer pain measure can also be determined in this manner.
  • the treatment provides 10%, 15%, 20%, 25%, 30%, 35% of patients with at least 30%, 50%, 70% or 90% improvement in cancer pain. In some embodiments, the treatment provides at least 20% of patients with at least 50% improvement in cancer pain at week 8 after start of treatment.
  • baseline refers to a value of a cancer pain associated measure for a patient prior to administration of tanezumab as part of the treatment method.
  • baseline refers to a value of a sign or symptom associated measure for control healthy subjects that do not have cancer pain.
  • treatment with tanezumab effectively improves cancer pain at at least 8 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 10 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 12 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 14 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 16 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 24 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 32 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 40 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 56 weeks after start of treatment with the antibody.
  • the cancer pain is moderate to severe.
  • Average pain and worst pain in the index bone metastasis cancer pain site, non index cancer pain sites and average pain in painful major joints can be assessed by the subject at approximately the same time each day (or each week) with an 11 -point Numeric Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain).
  • NRS Numeric Rating Scale
  • the subjects should describe their pain in the painful site during the past 24 hours by choosing the appropriate number from 0 to 10.
  • index bone metastasis cancer pain site The most painful site of bone metastasis is considered the index bone metastasis cancer pain site (interchangeably referred to as “index cancer pain site”). Subjects record daily pain ratings for the index bone metastasis cancer pain site.
  • the Patient Global Assessment (PGA) measure is a global evaluation that utilizes a 5-point Likert scale with a score of 1 being best (very good) and a score of 5 being worst (very poor).
  • Functional assessment tools based on performance such as the Eastern Cooperative Oncology Group (ECOG) Performance Status (Oken MM, Creech RH, Tormey DC, et al. Am J Clinical Oncology 1982; 5(6):649-55) are validated and widely used tools in cancer care.
  • the ECOG Performance Status instrument is rated on a 5- point scale, with lower scores representing higher functional status.
  • Kellgren-Lawrence x-ray grade is a method of classifying the severity of osteoarthritis (Kellgren and Lawrence., Ann Rheum Dis 2000: 16(4): 494-502).
  • ACR American College of Rheumatology
  • Rapidly progressive osteoarthritis of the hip was first described by Forestier in 1957 and subsequently described in a number of studies as atrophic osteoarthritis, rapidly destructive osteoarthritis, rapidly destructive arthropathy, rapidly progressive hip disease, or rapidly destructive coxarthrosis. Rapidly progressive hip osteoarthritis is characterized by subjects who typically present with hip pain, often severe, with radiographs that show rapid joint space narrowing as a result of chrondrolysis from a prior radiograph and, subsequently, an osteolytic phase with severe progressive atrophic bone destruction involving the femoral head and the acetabulum.
  • Radiographic assessments (x-rays) of both knees, both hips and both shoulders can be performed or obtained prior to treatment, at screening.
  • Other major joints exhibiting signs or symptoms suggestive of osteoarthritis may also be imaged.
  • a major joint is defined as a mobile synovial joint in the limbs such as shoulders, elbows, wrists, hips, knees, ankles and excluding the joints of the toes and hands. Any joint imaged at Screening or other at risk joints identified during the study period should also be imaged.
  • a central radiology reader may review the radiology images for assessment of eligibility including determination and identification of exclusionary joint conditions. Radiographs required at screening may be obtained at least two weeks and up to 32 days prior to the beginning of the Baseline Assessment Period (BAP) to permit central radiology review of the images and to establish subject eligibility for initial dosing with tanezumab. In some embodiments, subjects may not be permitted to start dosing with tanezumab until the screening radiographs are reviewed and eligibility is established.
  • BAP Baseline Assessment Period
  • the X-ray technologists in addition to their professional training and certifications, are trained in performing the radiographic protocols for the knees, hips, and shoulders.
  • a semi -automated software and positioning frame standardized subject and joint positioning protocol can be utilized.
  • the Core Imaging Laboratory may be responsible for working with the sites to ensure quality, standardization and reproducibility of the radiographic images/assessments made at the Screening and follow-up time-points. Additional details regarding the required X-rays may be provided in a site imaging manual.
  • Central radiology readers may be board certified radiologists or have the international equivalent as musculoskeletal radiologists.
  • the Central Readers may be governed by an imaging atlas and an imaging Charter which includes a specific description of the scope of their responsibilities.
  • Central Readers may review the radiology images at Screening for assessment of eligibility (including determination of Kellgren-Lawrence Grade) and identification of exclusionary joint conditions such as rapidly progressive osteoarthritis, atrophic or hypotrophic osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis and pathological fractures.
  • the Central Reader may review radiology images for diagnosis of joint conditions that would warrant further evaluation by the Adjudication Committee such as possible or probable rapidly progressive osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis or pathological fracture.
  • Adjudication Committee such as possible or probable rapidly progressive osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis or pathological fracture.
  • Patients may be excluded from treatment with tanezumab, during or before treatment with tanezumab, if there is radiographic evidence of any of the following conditions in any screening radiograph as determined by a central radiology reviewer and as defined in an imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; other arthropathies (e.g., rheumatoid arthritis), systemic metabolic bone disease (e.g., pseudogout, Paget’s disease; metastatic calcifications), large cystic lesions, primary or metastatic tumor lesions, stress or traumatic fracture.
  • excessive malalignment of the knee severe chondrocalcinosis
  • other arthropathies e.g., rheumatoid arthritis
  • systemic metabolic bone disease e.g., pseudogout, Paget’s disease
  • metastatic calcifications e.g., metastatic calcifications
  • large cystic lesions e.g., primary or metastatic
  • a patient may be excluded from treatment with tanezumab, before or during the treatment with tanezumab, if there is radiographic evidence of any of the following conditions as determined by the central radiology reviewer and as defined in an imaging atlas at screening: 1) rapidly progressive osteoarthritis, 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
  • SPONK spontaneous osteonecrosis of the knee
  • a patient may be excluded from treatment, before or during treatment, with tanezumab if the patient has been diagnosed as having osteoarthritis of the knee or hip as defined by the American College of Rheumatology (ACR) clinical and radiographic criteria; having Kellgren-Lawrence Grade >2 radiographic evidence of hip osteoarthritis; and/or having Kellgren-Lawrence Grade >3 radiographic assessment of knee osteoarthritis and/or having symptoms and radiographic evidence of osteoarthritis of the shoulder.
  • ACR American College of Rheumatology
  • the radiographic criteria may be assessed by a Central Reader.
  • a patient may be included for treatment with tanezumab according to the invention if the patient has one or more of a) cancer pain from cancer other than from breast cancer, prostate cancer or lung cancer metastasized to bone; b) an average pain score of about 6 at the index cancer pain site; c) a total weekly median opioid use of less than about 100 morphine equivalents; d) a tumor that is less aggressive as assessed by ECOG Performance Status (which may be less than or equal to 1); and e) no concomitant anti-cancer therapy.
  • the patient has two or more, three or more, four or more, or all of these characteristics.
  • a “patient”, an “individual” or a “subject”, used interchangeably herein, is a mammal, more preferably, a human. Mammals also include, but are not limited to, farm animals (e.g., cows, pigs, horses, chickens, etc.), sport animals, pets, primates, horses, dogs, cats, mice and rats.
  • farm animals e.g., cows, pigs, horses, chickens, etc.
  • sport animals e.g., pets, primates, horses, dogs, cats, mice and rats.
  • vector means a construct, which is capable of delivering, and, preferably, expressing, one or more gene(s) or sequence(s) of interest in a host cell.
  • vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.
  • expression control sequence means a nucleic acid sequence that directs transcription of a nucleic acid.
  • An expression control sequence can be a promoter, such as a constitutive or an inducible promoter, or an enhancer.
  • the expression control sequence is operably linked to the nucleic acid sequence to be transcribed.
  • pharmaceutically acceptable carrier or “pharmaceutical acceptable excipient” includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system.
  • examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents.
  • Preferred diluents for aerosol or parenteral administration are phosphate buffered saline (PBS) or normal (0.9%) saline.
  • Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).
  • effector function refers to the biological activities attributable to the Fc region of an antibody.
  • antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), Fc receptor binding, complement dependent cytotoxicity (CDC), phagocytosis, C1q binding, and down regulation of cell surface receptors (e.g., B cell receptor; BCR). See, e.g., U.S. Pat No. 6,737,056.
  • Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions.
  • An exemplary measurement of effector function is through Fcy3 and/or C1q binding.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcRs Fc receptors
  • NK natural killer cells
  • macrophages e.g. natural killer cells, neutrophils, and macrophages
  • ADCC activity of a molecule of interest can be assessed using an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or 5,821,337.
  • Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells.
  • PBMC peripheral blood mononuclear cells
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., 1998, PNAS (USA), 95:652- 656.
  • “Complement dependent cytotoxicity” or “CDC” refers to the lysing of a target in the presence of complement.
  • the complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g. an antibody) complexed with a cognate antigen.
  • a CDC assay e.g. as described in Gazzano-Santoro et al., J. Immunol. Methods, 202: 163 (1996), may be performed.
  • kon refers to the rate constant for association of an antibody to an antigen. Specifically, the rate constants (kon or ka and koff or kd) and equilibrium dissociation constants are measured using whole antibody (i.e. bivalent) and monomeric proteins.
  • koff or “kd”, as used herein, refers to the rate constant for dissociation of an antibody from the antibody/antigen complex.
  • KD refers to the equilibrium dissociation constant of an antibody-antigen interaction.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • description referring to “about X” includes description of “X.”
  • Numeric ranges are inclusive of the numbers defining the range.
  • the term “about” refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g. within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater.
  • the term “about” is used within the context of a time period (years, months, weeks, days etc.)
  • the term “about” means that period of time plus or minus one amount of the next subordinate time period (e.g. about 1 year means 11-13 months; about 6 months means 6 months plus or minus 1 week; about 1 week means 6-8 days; etc.), or within 10 per cent of the indicated value, whichever is greater.
  • subcutaneous administration refers to the administration of a substance into the subcutaneous layer.
  • preventing refers to (a) keeping a disorder from occurring or (b) delaying the onset of a disorder or onset of symptoms of a disorder.
  • the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members.
  • the present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.
  • tanezumab for use in the methods of treatment as described herein.
  • Tanezumab is a humanized immunoglobulin G Type 2 (lgG2) monoclonal antibody, derived from a murine precursor with a mutation in the Fc portion of the antibody to decrease its ability to activate complement or to support antibody dependent cell- mediated cytotoxicity. Tanezumab is highly potent in sequestering NGF and preventing interaction with the trkA or p75 receptors.
  • Exemplary antibody sequences for tanezumab include, but are not limited to, the sequences listed below.
  • the antibodies as described herein can be made by any method known in the art.
  • An antibody may be made recombinantly using a suitable host cell.
  • a nucleic acid encoding an anti-NGF antibody of the present disclosure can be cloned into an expression vector, which can then be introduced into a host cell, where the cell does not otherwise produce an immunoglobulin protein, to obtain the synthesis of an antibody in the recombinant host cell.
  • Any host cell susceptible to cell culture, and to expression of protein or polypeptides may be utilized in accordance with the present invention.
  • the host cell is mammalian. Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC).
  • ATCC American Type Culture Collection
  • Nonlimiting exemplary mammalian cells include, but are not limited to, NS0 cells, HEK 293 and Chinese hamster ovary (CHO) cells, and their derivatives, such as 293-6E and CHO DG44 cells, CHO DXB11, and Potelligent® CHOK1SV cells (BioWa/Lonza, Allendale, NJ).
  • Mammalian host cells also include, but are not limited to, human cervical carcinoma cells (HeLa, ATCC CCL 2), baby hamster kidney (BHK, ATCC CCL 10) cells, monkey kidney cells (COS), and human hepatocellular carcinoma cells (e.g., Hep G2).
  • monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1 587); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TR1 cells (Mather et al., Annals N.Y. Acad. Sci.
  • MRC 5 cells MRC 5 cells; FS4 cells; a human hepatoma line (Hep G2); and numerous myeloma cell lines, including, but not limited to, BALB/c mouse myeloma line (NS0/1, ECACC No: 85110503), NS0 cells and Sp2/0 cells.
  • FS4 cells a human hepatoma line (Hep G2)
  • numerous myeloma cell lines including, but not limited to, BALB/c mouse myeloma line (NS0/1, ECACC No: 85110503), NS0 cells and Sp2/0 cells.
  • any number of commercially and non-commercially available cell lines that express polypeptides or proteins may be utilized.
  • different cell lines might have different nutrition requirements and/or might require different culture conditions for optimal growth and polypeptide or protein expression and will be able to modify conditions as needed.
  • the route and schedule of immunization of the host animal are generally in keeping with established and conventional techniques for antibody stimulation and production, as further described herein.
  • General techniques for production of human and mouse antibodies are known in the art and/or are described herein.
  • any mammalian subject including humans or antibody producing cells therefrom can be manipulated to serve as the basis for production of mammalian, including human and hybridoma cell lines.
  • the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantar, and/or intradermally with an amount of immunogen, including as described herein.
  • Hybridomas can be prepared from the lymphocytes and immortalized myeloma cells using the general somatic cell hybridization technique of Kohler, B. and Milstein, C., Nature 256:495-497, 1975 or as modified by Buck, D. W., et al., In Vitro, 18:377-381 , 1982.
  • Available myeloma lines including but not limited to X63-Ag8.653 and those from the Salk Institute, Cell Distribution Center, San Diego, Calif., USA, may be used in the hybridization.
  • the technique involves fusing myeloma cells and lymphoid cells using a fusogen such as polyethylene glycol, or by electrical means well known to those skilled in the art.
  • the cells are separated from the fusion medium and grown in a selective growth medium, such as hypoxanthine-aminopterin-thymidine (HAT) medium, to eliminate unhybridized parent cells.
  • a selective growth medium such as hypoxanthine-aminopterin-thymidine (HAT) medium
  • HAT hypoxanthine-aminopterin-thymidine
  • Any of the media described herein, supplemented with or without serum, can be used for culturing hybridomas that secrete monoclonal antibodies.
  • EBV immortalized B cells may be used to produce the monoclonal antibodies of the subject invention.
  • hybridomas are expanded and subcloned, if desired, and supernatants are assayed for anti-immunogen activity by conventional immunoassay procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay).
  • immunoassay procedures e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay.
  • Hybridomas that may be used as source of antibodies encompass all derivatives, progeny cells of the parent hybridomas that produce monoclonal antibodies.
  • Hybridomas that produce antibodies used for the present invention may be grown in vitro or in vivo using known procedures.
  • the monoclonal antibodies may be isolated from the culture media or body fluids, by conventional immunoglobulin purification procedures such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration, if desired.
  • Undesired activity, if present, can be removed, for example, by running the preparation over adsorbents made of the immunogen attached to a solid phase and eluting or releasing the desired antibodies off the immunogen.
  • a protein that is immunogenic in the species to be immunized e.g., keyhole
  • the antibody (monoclonal or polyclonal) of interest may be sequenced and the polynucleotide sequence may then be cloned into a vector for expression or propagation.
  • the sequence encoding the antibody of interest may be maintained in vector in a host cell and the host cell can then be expanded and frozen for future use.
  • Production of recombinant monoclonal antibodies in cell culture can be carried out through cloning of antibody genes from B cells by means known in the art. See, e.g. Tiller et al., J. Immunol. Methods 329, 112, 2008; U.S. Pat. No. 7,314,622.
  • antibodies may be made using hybridoma technology. It is contemplated that any mammalian subject including humans or antibody producing cells therefrom can be manipulated to serve as the basis for production of mammalian, including human, hybridoma cell lines.
  • the route and schedule of immunization of the host animal are generally in keeping with established and conventional techniques for antibody stimulation and production, as further described herein.
  • the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantar, and/or intradermally with an amount of immunogen, including as described herein.
  • antibodies as described herein are glycosylated at conserved positions in their constant regions (Jefferis and Lund, 1997, Chem. Immunol. 65:111-128; Wright and Morrison, 1997, TibTECH 15:26-32).
  • the oligosaccharide side chains of the immunoglobulins affect the protein’s function (Boyd et al., 1996, Mol. Immunol. 32:1311-1318; Wittwe and Howard, 1990, Biochem. 29:4175-4180) and the intramolecular interaction between portions of the glycoprotein, which can affect the conformation and presented three-dimensional surface of the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, 1996, Current Opin. Biotech. 7:409-416).
  • Oligosaccharides may also serve to target a given glycoprotein to certain molecules based upon specific recognition structures. Glycosylation of antibodies has also been reported to affect antibody-dependent cellular cytotoxicity (ADCC).
  • ADCC antibody-dependent cellular cytotoxicity
  • antibodies produced by CHO cells with tetracycline-regulated expression of b(1,4)-N- acetylglucosaminyltransf erase III (GnTIII), a glycosyltransf erase catalyzing formation of bisecting GlcNAc was reported to have improved ADCC activity (Umana et al., 1999, Nature Biotech. 17:176-180).
  • N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
  • the tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
  • O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
  • glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above- described tripeptide sequences (for N-linked glycosylation sites).
  • the alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).
  • glycosylation pattern of antibodies may also be altered without altering the underlying nucleotide sequence. Glycosylation largely depends on the host cell used to express the antibody. Since the cell type used for expression of recombinant glycoproteins, e.g. antibodies, as potential therapeutics is rarely the native cell, variations in the glycosylation pattern of the antibodies can be expected (see, e.g. Hse et al., 1997, J. Biol. Chem. 272:9062-9070).
  • factors that affect glycosylation during recombinant production of antibodies include growth mode, media formulation, culture density, oxygenation, pH, purification schemes and the like.
  • Various methods have been proposed to alter the glycosylation pattern achieved in a particular host organism including introducing or overexpressing certain enzymes involved in oligosaccharide production (U.S. Patent Nos. 5,047,335; 5,510,261 and 5,278,299).
  • Glycosylation or certain types of glycosylation, can be enzymatically removed from the glycoprotein, for example, using endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, endoglycosidase F3.
  • Endo H endoglycosidase H
  • N-glycosidase F N-glycosidase F
  • endoglycosidase F1 endoglycosidase F2
  • endoglycosidase F3 endoglycosidase F3
  • the recombinant host cell can be genetically engineered to be defective in processing certain types of polysaccharides.
  • Modifications include using coupling techniques known in the art, including, but not limited to, enzymatic means, oxidative substitution and chelation. Modifications can be used, for example, for attachment of labels for immunoassay. Modified polypeptides are made using established procedures in the art and can be screened using standard assays known in the art, some of which are described below and in the Examples.
  • the invention also provides polynucleotides encoding any of the anti-NGF antibodies as described herein. In one aspect, the invention provides a method of making any of the polynucleotides described herein. Polynucleotides can be made and expressed by procedures known in the art.
  • the invention provides compositions (such as a pharmaceutical compositions) comprising any of the polynucleotides of the invention.
  • the composition comprises an expression vector comprising a polynucleotide encoding any of the anti-NGF antibodies described herein.
  • an isolated cell line that produces the anti-NGF antibodies as described herein.
  • Polynucleotides complementary to any such sequences are also encompassed by the present invention.
  • Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNAor synthetic) or RNA molecules.
  • RNA molecules include FlnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.
  • Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes an antibody or a fragment thereof) or may comprise a variant of such a sequence.
  • Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not diminished, relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide may generally be assessed as described herein.
  • Variants preferably exhibit at least about 70% identity, more preferably, at least about 80% identity, yet more preferably, at least about 90% identity, and most preferably, at least about 95% identity to a polynucleotide sequence that encodes a native antibody or a fragment thereof.
  • Two polynucleotide or polypeptide sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity.
  • a “comparison window” as used herein refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, or 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • Optimal alignment of sequences for comparison may be conducted using the MegAlign ® program in the Lasergene ® suite of bioinformatics software (DNASTAR ® , Inc., Madison, Wl), using default parameters.
  • This program embodies several alignment schemes described in the following references: Dayhoff, M.O., 1978, A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol.
  • the "percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences.
  • the percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.
  • Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof.
  • Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementary sequence).
  • Suitable “moderately stringent conditions” include prewashing in a solution of 5 X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50°C-65°C, 5 X SSC, overnight; followed by washing twice at 65°C for 20 minutes with each of 2X, 0.5X and 0.2X SSC containing 0.1 % SDS.
  • highly stringent conditions or “high stringency conditions” are those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at42°C; or (3) employ 50% formamide, 5 x SSC (0.75 M NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt’s solution, sonicated salmon sperm DNA (50 pg/ml), 0.1% SDS, and 10% dextran sulfate at
  • nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).
  • polynucleotides of this invention can be obtained using chemical synthesis, recombinant methods, or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of skill in the art can use the sequences provided herein and a commercial DN A synthesizer to produce a desired DNA sequence.
  • a polynucleotide comprising a desired sequence can be inserted into a suitable vector, and the vector in turn can be introduced into a suitable host cell for replication and amplification, as further discussed herein.
  • Polynucleotides may be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome.
  • the polynucleotide so amplified can be isolated from the host cell by methods well known within the art. See, e.g., Sambrook et al., 1989.
  • PCR allows reproduction of DNA sequences.
  • PCR technology is well known in the art and is described in U.S. Patent Nos. 4,683,195, 4,800,159, 4,754,065 and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.
  • RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those of skill in the art, as set forth in Sambrook et al., 1989, supra, for example.
  • Suitable cloning vectors may be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones containing the vector.
  • Suitable examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBSSK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28.
  • plasmids and bacterial viruses e.g., pUC18, pUC19, Bluescript (e.g., pBSSK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28.
  • Expression vectors are further provided.
  • Expression vectors generally are replicable polynucleotide constructs that contain a polynucleotide according to the invention. It is implied that an expression vector must be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno- associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO 87/04462.
  • Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional controlling elements (such as promoters, enhancers and terminator). For expression (i.e., translation), one or more translational controlling elements are also usually required, such as ribosome binding sites, translation initiation sites, and stop codons.
  • the vectors containing the polynucleotides of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation, transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipofection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus).
  • electroporation employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances
  • microprojectile bombardment e.g., where the vector is an infectious agent such as vaccinia virus.
  • infection e.g., where the vector is an infectious agent such as vaccinia virus.
  • the choice of introducing vectors or polynucleotides will often depend on features of the host cell.
  • the invention also provides host cells comprising any of the polynucleotides described herein. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest.
  • mammalian host cells include but not limited to COS, HeLa, and CHO cells. See also PCT Publication No. WO 87/04462. Suitable non mammalian host cells include prokaryotes (such as E. coli or B. subtiHis) and yeast (such as S. cerevisae, S. pombe or K. lactis ).
  • the host cells express the cDNAs at a level of about 5 fold higher, more preferably, 10 fold higher, even more preferably, 20 fold higher than that of the corresponding endogenous antibody or protein of interest, if present, in the host cells. Screening the host cells for a specific binding to NGFis effected by an immunoassay or FACS. A cell overexpressing the antibody or protein of interest can be identified.
  • the invention also provides pharmaceutical compositions comprising an effective amount of tanezumab as described herein, and such pharmaceutical compositions for use in methods of treatment as described herein. Examples of such compositions, as well as how to formulate, are also described herein.
  • compositions can comprise more than one anti-NGF antibody.
  • composition used in the present invention can further comprise pharmaceutically acceptable carriers, excipients, or stabilizers (Remington: The Science and practice of Pharmacy 20th Ed., 2000, Lippincott Williams and Wilkins, Ed. K. E. Floover), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • Tanezumab, and compositions thereof can also be used in conjunction with, or administered separately, simultaneously, or sequentially with other agents that serve to enhance and/or complement the effectiveness of the agents.
  • the invention provides a method for treating cancer pain in a patient as defined herein.
  • the methods described herein further comprise a step of treating a subject with an additional form of therapy.
  • the method described herein does not comprise administration of an NSAID to the patient. In some embodiments, the method described herein does not comprise administration of an opioid to the patient.
  • compositions comprising one or more additional agents.
  • These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients including buffers, which are well known in the art.
  • suitable excipients such as pharmaceutically acceptable excipients including buffers, which are well known in the art.
  • the present invention can be used alone or in combination with other methods of treatment.
  • an anti-NGF antibody may be used for administration.
  • Pharmaceutically acceptable excipients are known in the art, and are relatively inert substances that facilitate administration of a pharmacologically effective substance.
  • an excipient can give form or consistency, or act as a diluent.
  • Suitable excipients include but are not limited to stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, buffers, and skin penetration enhancers.
  • Excipients as well as formulations for parenteral and nonparenteral drug delivery are set forth in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000.
  • these agents are formulated for administration by injection (e.g., intraperitoneally, intravenously, subcutaneously, intramuscularly, intraarticularly, epidurally, intrathecally, injection into the intervertebral disc, etc.). Accordingly, these agents can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like.
  • pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like.
  • the particular dosage regimen i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history.
  • tanezumab is administered in a formulation described in WO201 0/032220, herein incorporated by reference.
  • the formulation is a liquid formulation and comprises an anti-NGF antibody at a concentration of about 20 mg/ml; and a histidine buffer.
  • the formulation further comprises a surfactant which may be polysorbate 20. In some embodiments, the formulation further comprises trehalose dehydrate or sucrose. In some embodiments, the formulation further comprises a chelating agent, which may be EDTA; in some embodiments disodium EDTA. In some embodiments, the formulation is of pH 6.0 ⁇ 0.3.
  • the formulation comprises about 20 mg/ml tanezumab; about 10 mM histidine buffer; about 84 mg/ml trehalose dehydrate; about 0.1 mg/ml Polysorbate 20; about 0.05 mg/mldisodium EDTA; wherein the formulation is of a pH 6.0 ⁇ 0.3.
  • the formulation has a total volume of about 1 ml.
  • the formulation is contained in a glass or plastic vial or syringe. In some embodiments the formulation is contained in a pre-filled glass or plastic vial or syringe.
  • Tanezumab can be administered every eight weeks. For repeated administrations over several doses, the treatment is sustained until a desired suppression of signs and symptoms of cancer pain occurs. The progress of this therapy can be monitored by conventional techniques and assays.
  • the dosing regimen can vary over time.
  • the dosage is 20 mg administered every eight weeks.
  • the dosage can be decreased or increased subsequent administrations.
  • the dosage of 20 mg can be administered at start of therapy and then a dosage of 10 mg can be administered at eight weeks, with a dosage of 10 mg being administered at sixteen weeks and each subsequent eight weekly dosage.
  • the dosage of 20 mg can be administered at start of therapy and at eight weeks, with a dosage of 10 mg being administered at sixteen weeks and each subsequent eight weekly dosage.
  • the 20 mg dosage can be administered at start of therapy and then for one, two, or more eight weekly dosages before subsequent dosages of 10 mg every eight weeks are administered.
  • a loading dose (or induction dose) is administered followed by the administration of maintenance doses at a lower amount or at lower frequency.
  • Administration of tanezumab as described herein in accordance with the method in the present invention can be continuous or intermittent, depending, for example, upon the recipient’s physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • the administration of tanezumab may be essentially continuous over a preselected period of time or may be in a series of spaced doses.
  • more than one anti-NGF antibody may be present. At least one, at least two, at least three, at least four, at least five different, or more anti-NGF antibodies can be present. Generally, those anti-NGF antibodies may have complementary activities that do not adversely affect each other.
  • tanezumab may be administered in combination with the administration of one or more additional therapeutic agents.
  • tanezumab administration is combined with a treatment regimen further comprising a traditional therapy including surgery.
  • Therapeutic formulations of the anti-NGF antibody used in accordance with the present invention are prepared for storage by mixing the protein having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine,
  • Liposomes containing the anti-NGF antibody are prepared by methods known in the art, such as described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
  • PEG-PE PEG-derivatized phosphatidylethanolamine
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and 7 ethyl-L- glutamate copolymers of L-glutamic acid and 7 ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.
  • the formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
  • Therapeutic anti-NGF antibody compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • compositions according to the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, ora non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanTM 20, 40, 60, 80 or 85).
  • Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
  • Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and LipiphysanTM.
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water.
  • an oil e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g. egg phospholipids, soybean phospholipids or soybean lecithin
  • other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion.
  • Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.
  • the emulsion compositions can be those prepared by mixing an anti-NGF antibody with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • such embodiments are also further embodiments of tanezumab for use in that treatment, or alternatively of the use of tanezumab in the manufacture of a medicament for use in that treatment.
  • Kits The invention also provides kits comprising tanezumab described herein.
  • Kits of the invention include one or more containers comprising tanezumab and instructions for use in accordance with any of the methods of the invention described herein. Generally, these instructions comprise a description of administration of the anti-NGF antibody for the above described therapeutic treatments.
  • kits are provided for producing a single-dose administration unit.
  • the kit can contain both a first container having a dried protein and a second container having an aqueous formulation.
  • kits containing single and multi-chambered pre-filled syringes are included.
  • the instructions relating to the use of the anti-NGF antibody generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • kits of this invention are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
  • packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump.
  • a kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • At least one active agent in the composition is an anti-NGF antibody.
  • the container may further comprise a second pharmaceutically active agent.
  • Kits may optionally provide additional components such as buffers and interpretive information.
  • the kit comprises a container and a label or package insert(s) on or associated with the container.
  • Example 1 The study was a randomized, double-blind, placebo-controlled, multicenter, parallel- group, 48-week Phase 3 study in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy.
  • Eligible subjects had cancer diagnosed as having metastasized to bone or had multiple myeloma with imaging confirmation of bone metastasis at Screening or within 120 days prior to the Screening visit according to local standard of care (e.g., via bone scan, magnetic resonance imaging (MRI), computed tomography (CT) scan, or positron emission tomography- computed tomography (PET-CT) scan).
  • MRI magnetic resonance imaging
  • CT computed tomography
  • PET-CT positron emission tomography- computed tomography
  • Subjects were required to have an average pain score >5 at Screening and Baseline for the index bone metastasis cancer pain site, a Patient’s Global Assessment of Cancer Pain assessed as ‘fair’, ‘poor’ or ‘very poor’ at Screening and at Baseline, and an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1 , or 2 at Screening. Subjects were expected to require daily opioid medication throughout the course of the study.
  • the protocol was initially designed to include 3 treatment groups (tanezumab 20 mg SC, tanezumab 10 mg SC, and placebo) with a 1 :1 :1 randomization ratio, but was amended (Amendment 3) after study start to discontinue the tanezumab 10 mg dose arm.
  • 3 treatment groups tanezumab 20 mg SC, tanezumab 10 mg SC, and placebo
  • Amendment 3 placebo
  • the opioid regimen for each subject was optimized prior to Baseline. Subjects on a stable opioid regimen who met the criteria for randomization during the Baseline Assessment Period continued on the same opioid regimen with only minimal dosage increases ( ⁇ 10% of baseline total daily dose) permitted for the first 8 weeks of the Double-Blind Treatment Period.
  • Stratification variables were (i) tumor aggressiveness (assessed by ECOG performance status) and (ii) presence/absence of concomitant anticancer treatment (e.g., chemotherapy or hormonal therapy or anti hormonal therapy).
  • the primary efficacy endpoint was measured 8 weeks after the 1st dose at Baseline. The end of the double-blind treatment period was at Week 24, followed by a 24-week safety follow-up period, resulting in the end of study at Week 48.
  • the study had a Group Sequential Design with a single interim analysis performed after at least 50% of subjects had completed or discontinued prior to Week 8. The interim analysis assessed both futility (non-binding) and efficacy based on the primary efficacy parameter. The study did not stop based on the interim analysis.
  • the alpha used for final analysis was not 0.05, but was determined based on the number of subjects included in the interim analysis and in the final analysis using the Lan DeMets alpha spending function with the O’Brien Fleming style boundary, which was implemented in EAST version 6.5.
  • the alpha-level used for a two-sided test of the primary endpoint in the final analysis was 0.0478.
  • the primary analysis set for efficacy is the modified intent to treat (mITT) analysis set. It is labeled as the “mITT Population” and consists of all subjects who were randomized to either tanezumab 20 mg or placebo SC and received at least one dose of SC study medication.
  • the safety analysis set is defined as all subjects treated with tanezumab or placebo SC and is labeled as the ‘Safety Analysis Set’ or ‘Safety Population’. This set also includes 10 subjects who were randomized and received tanezumab 10 mg: 9 remained on tanezumab 10 mg SC and 1 changed to tanezumab 20 mg SC after the implementation of Amendment 3.
  • Table 2 Summary of Subject Evaluation and Disposition Events for Placebo and Tanezumab 20 mg (Primary Analysis Set)
  • Primary Endpoint Change from Baseline to Week 8 in Average Pain Intensity at the Index Cancer Pain Site.
  • Treatment with tanezumab 20 mg SC resulted in significant improvement (reduction) in the daily average pain intensity score compared to placebo treatment and met the primary objective of the study.
  • the type-l error (alpha-level) for the final analysis was determined based on the pre-specified Lan-DeMets alpha-spending function with the O’Brien Fleming style boundary.
  • the alpha-level used for a two-sided test of the primary endpoint in the final analysis of the 145 subjects was 0.0478.
  • the worst pain intensity score at the index cancer pain site also showed greater average improvement (LS mean, 95% Cl) in the tanezumab 20 mg group than in the placebo group, statistically significant at Weeks 2, 4 and 6 ( Figure 3B).
  • the mean (median) daily dosage of opioids was 183 (90) Milligram Morphine Equivalent (MME) in the placebo group, and 190 (85) MME in the tanezumab 20 mg group.
  • the average daily dosage remained between 170 and 190 MME for both groups through Week 16.
  • the mean (SD) daily dosage of opioids was 190 (353) MME in the placebo group, and 347 (1537) MME in the tanezumab 20 mg group.
  • the higher dose in the tanezumab group was due to an extreme value of 12746 MME.
  • the median daily dose at Week 24 was 61 MME in both treatment groups.
  • the rescue medication was used on average 0.92 times per day in the tanezumab 20 mg group and 1.26 times/day in the placebo group. After baseline, rescue medication continued to be used less frequently in the tanezumab 20 mg group than in the placebo group, ranging from 25% (95% Cl: 4%- 42%) less at Week 4 to 10% less at Week 24. Subgroup Analysis
  • carcinoma Primary cancer type (breast carcinoma, lung carcinoma, prostatic carcinoma, and other carcinomas o Other carcinomas (pooled subjects for carcinomas with fewer that 10 subjects in both the tanezumab 20 mg and placebo treatment groups) including bone marrow, bone metastasis, cervical cancer, cholangiocarcinoma, colorectal carcinoma, corpus uteri carcinoma, gastric carcinoma, head of pancreas carcinoma, larynx epidermoid carcinoma, myeloma, nasopharynx carcinoma, pancreatic neuroendocrine tumors, rectal carcinoma, renal carcinoma, sublingual gland cancer, and uterine carcinoma
  • the safety population consisted of 73 subjects in the placebo SC group, 72 subjects in the tanezumab 20 mg SC group, 9 subjects who received tanezumab 10 mg SC, and 1 subject in the tanezumab 10/20 mg SC group.
  • the proportion of subjects that received three planned SC doses of study medication were 52.1%, 65.3%, and 66.7% in the placebo, tanezumab 20 mg, and tanezumab 10 mg treatment groups, respectively.
  • Treatment-emergent adverse events are shown in Table 4.
  • the incidence of adverse events was 68.5% in the placebo group, 73.6% in the tanezumab 20 mg group, 88.9% (8 of 9) in the tanezumab 10 mg group and 100% (1 of 1) in the tanezumab 10/20 mg group.
  • the incidence of serious adverse events was 30.1% (placebo group), 40.3% (tanezumab 20 mg group), 22.2% (2 of 9, tanezumab 10 mg group) and 100% (1 of 1, tanezumab 10/20 mg group).
  • the total number of deaths reported in the study was 46 and none was considered treatment-related by the investigators.
  • Tanezumab 20 mg demonstrated significantly greater improvements vs placebo in the daily average pain intensity and in the daily worst pain intensity in the index bone metastasis cancer pain site at Weeks 2, 4 and 6. Tanezumab 20 mg also demonstrated a significantly greater proportion of subjects with a 50% response at Week 8 compared to placebo.
  • the safety findings including the adverse event profile in the tanezumab treatment groups were generally consistent with those anticipated in subjects with cancer pain predominantly due to bone metastasis and/or the known safety profile of tanezumab.

Abstract

The present invention relates to the treatment of cancer pain predominantly due to bone metastasis with an anti-nerve growth factor (NGF) antibody.

Description

METHOD OF TREATMENT OF CANCER PAIN WITH TANEZUMAB
Field
The present invention relates to the treatment of cancer pain with tanezumab, an anti-nerve growth factor (NGF) antibody.
Background
With improved medical treatment of many cancers, patients are living longer, which places them at increased risk to develop metastatic disease. The skeleton is the third most common target of metastatic cancer and can be one of the earliest sites affected (Schulman KL, Kohle J. Cancer 2007; 109(11):2334-42).
Cancers of the breast and prostate are particularly likely to spread to bone; about 70% of patients who die from these diseases have evidence of skeletal involvement at autopsy.
Carcinomas of the thyroid, kidney, and bronchus also often cause bone metastasis with a post-mortem incidence of 30% to 40%, but, by contrast, tumors of the gastrointestinal tract do so rarely, affecting only about 5% of patients dying from these malignancies. Given the high prevalence of carcinomas of the breast, prostate, and lung, it is estimated that these cancers probably account for more than 80% of cases of metastatic bone disease (Rubens RD. European Journal of Cancer 1998; 34(2):210- 13).
For many patients, metastatic bone cancer is a chronic condition, with survival from the time of diagnosis varying significantly among the various tumor types. For bone metastasis from prostate and breast and in multiple myeloma, median survival time from diagnosis is measurable in years. For advanced lung cancer, it is usually measured in months (Upton A, Berenson JR, Body JJ, et al. Clin Cancer Res 2006; 12(20 Suppl) 6209s- 12s).
Pain associated with cancer is a substantial problem that negatively impacts patients’ quality of life, especially as emerging therapies directed against the underlying cancer have begun to prolong patient survival. While pain can result from a number of causes, bone metastasis is the most common cause of cancer pain, occurring in 60 to 84% of patients (Langford DJ, Tripathy D, Paul SM, et al. Journal of Pain 2011 ; 12(4):495-507; Mercadante S. Pain 1997; 69:1-18). More than 70% of patients with bone metastasis report moderate to severe pain that has a significant impact on their functional status and quality of life (Langford DJ, Tripathy D, Paul SM, et al. Journal of Pain 2011 ; Yau V, Chow E, Davis L, et al. J Pain Symptom Management 2004; 27(1 ):1 -3. 17; Rustoen T, Mourn T, Padilla G, et al. J Pain Symptom Management 2005 30(3):234-42).
Treatment of bone metastasis is primarily palliative, in order to relieve pain, prevent development of pathological fractures and improve mobility and function (Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011 ; 16(3)441-58; Houston SJ, Rubens RD. Clin Orthop Relat Res 1995; 312:539-42). Conventional treatment uses a multidisciplinary approach including local radiotherapy to the painful area along with systemic treatment (hormone therapy or chemotherapy or radioisotopes) and supportive care such as analgesic therapy, corticosteroids and bisphosphonates (Mercadante F, Fulfaro F. Curr Opin Oncol 2007; 19:308-14. 21 ; Goldberg G, Morrison R. J Clin Oncol 2007; 25:1792-1801. Unfortunately, chronic pain resulting from bone metastasis is relatively resistant to analgesics; therefore, its management remains a challenge for clinicians (Yau V, Chow E, Davis L, et al. J Pain Symptom Management 2004; 27(1 ):1 -3; Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011 ; 16(3)441-58).
The basic approach to cancer pain treatment was designed by the World Health Organization (WHO) in 1986 and was subsequently revised in 1996 (World Health Organization. Cancer Pain Relief 1996; 2nd edition Geneva: World Health Organization). This approach uses a 3-step analgesic ladder in which patients begin treatment with non-opioids and move up the ladder to mild opioids and finally to strong opioids if their pain is not sufficiently controlled by analgesic treatments in the first step(s) of the ladder. Since the initial WHO publication, other groups have issued guidelines for management of cancer (Management of cancer pain guideline overview. Agency for Healthcare Policy and Research Rockville, Maryland. J Natl Med Assoc 1994; 86:571-73, 634; Gordon DB, Dahl JL, Miaskowski C, et.al. Arch Intern Med 2005; 165:1574-80; Benedetti C, Brock C, Cleeland C, et al. Oncology (Williston Park) 2000; 14:135-50; National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines In Oncology. Adult Cancer Pain Version 2.2013:1-75). Overall, there has been increasing use of opioids for management of cancer pain and opioids remain the mainstay for treatment of moderate to severe cancer pain.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer-related bone pain has been questioned since the evidence in the medical literature is poor. In addition, there is a possibility that NSAIDs and cyclooxygenase (COX)-2 inhibitors could affect bone health by inhibiting COX enzymes which reduce synthesis of prostaglandins (Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011; 16(3)441-58).
Recent investigations have shown that opioids may impair bone metabolism and chronic opioid users have an increased risk of fractures (Coluzzi F, Mandatori I, Mattia C. Expert Opin. Emerging Drugs 2011 ; 16(3)441-58; Buckeridge D, Fluang A, Hanley J, et al. J Am Geriatr Soc 2010; 58:1664-70). In addition, recent publications seem to hint that opioids may have a possible role in tumor progression (Lennon FE, Moss J, Singleton PA. Anesthesiology 2012; 116(4):940-45).
Despite the widespread use of opioids, results of a recent systematic review of current literature for randomized controlled trials of opioids for management of cancer pain noted the level of evidence for pain relief was only fair for transderm al fentanyl and was poor for morphine, tramadol, oxycodone, methadone and codeine (Koyyalagunta D, Bruera E, Solanki D, et al. Pain Physician 2012; 15:ES39-ES58). A 10-year validation study of the World Health Organization analgesic ladder in 1995 (Zech DF, Grond S, Lynch J, et al. Pain 1995; 63:65-76) suggested that 76% of patients could achieve good pain relief using the principles of the ladder, a further 12% achieved satisfactory efficacy and 12% had inadequate efficacy. Unfortunately, subsequent studies suggest that these results are not achieved in clinical practice and that much cancer pain continues to be poorly controlled (Forbes K. Clinical Oncology 2011 ; 23:379-80).
The issues described above support the need for better treatments for patients suffering from metastatic bone pain. Tanezumab is an anti-NGF antibody that binds to and inhibits the actions of nerve growth factor (NGF). The Nerve Growth Factor Inhibitor (NGFI) class may offer an important breakthrough in the treatment of chronic pain and has undergone clinical investigation for the treatment of pain associated with osteoarthritis or other chronic pain conditions.
The efficacy of tanezumab in subjects with painful bone metastasis was evaluated in the Phase 2 Study A4091003, which was a randomized, double-blind, placebo- controlled, parallel group study in subjects with cancer pain due to bone metastasis who were receiving background treatment with opioids. In addition, subjects who had been randomized and treated in Study A4091003, and who wished to receive open-label tanezumab therapy, could roll over to Study A4091029, a safety extension study designed to investigate the safety and maintenance of effect of tanezumab 10 mg. In Study A4091003, a total of 59 patients were treated with either a single intravenous (IV) dose of tanezumab 10 mg (N=29) or placebo (N=30). In Study A4091029, a total of 41 patients were treated with tanezumab 10 mg IV. A positive outcome for the primary efficacy endpoint for Study A4091003 (i.e., a statistically significant change from Baseline to Week 6 in the daily average pain intensity) was not achieved, although the mean decrease from Baseline in the tanezumab 10 mg IV treatment group was numerically greater than that for the placebo treatment group. The change from Study A4091003 Baseline in average pain was maintained up to Week 24 in A4091029 for all subjects. For the 6 subjects who had received placebo in Study A4091003, the average pain score in A4091029 subsequently worsened from Week 24 to Week 40 (back to the Study A4091003 Baseline pain level). Flowever, for subjects who had received tanezumab 10 mg in Study A4091003, the improvement in average pain was further maintained to Week 40 of Study A4091029.
Although an acceptable safety profile was seen in the previous studies in this patient population, efficacy has not yet been robustly demonstrated, hence further evaluation of benefit-risk is required. Summary
The invention disclosed herein is directed to treatment of cancer pain predominantly due to bone metastases in patients receiving background opioid therapy.
Accordingly, in one aspect, the invention provides a method of treating cancer pain in a patient in need thereof, the method comprising administering 20 mg of tanezumab subcutaneously to the patient, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis, cancer originated in bone, or multiple myeloma, and wherein the patient has had inadequate pain relief with opioid analgesics.
In some embodiments, the patient has: i. an average Pain Score of at least 5 for the index cancer pain site; ii. a Patient's Global Assessment of Cancer Pain of "fair", "poor" or "very poor"; iii. an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1, or 2; and iv. no joint safety event selected from: 1) rapidly progressive osteoarthritis (type 1 or type 2), 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fracture, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
Clinical benefit of the treatment according to the invention effectively reduces pain at the index cancer pain site.
In some embodiments, tanezumab is administered every eight weeks. In some embodiments, tanezumab is administered for at least two or more doses at eight weekly intervals. In some embodiments, tanezumab is administered to the patient for at least 8, 16, 24, 32, 40 or 48 weeks.
In some embodiments, the treatment effectively reduces average pain intensity at the index cancer pain site; effectively reduces worst pain intensity at the index cancer pain site; and/or effectively reduces patient global assessment of cancer pain at the index cancer pain site.
In some embodiments, the treatment effectively reduces pain at the index cancer pain site at at least 1, 2, 3, 4, 5, 6, 7, or 8 week(s) after start of treatment. In some embodiments, the treatment effectively reduces pain at the index cancer pain site at weeks 2, 4, and 6, in addition to week 8 after start of treatment. In some embodiments, the treatment effectively reduces pain at the index cancer pain site at at least 16, 24, 32, 40, 48 or 56 weeks after start of treatment.
In some embodiments, the treatment effectively improves pain at the index cancer pain site compared to a baseline value prior to or at start of treatment.
In some embodiments, the patient requires background opioid therapy and/or may require opioid medication. The patient may require daily opioid medication. In some embodiments, the treatment results in reduced opioid use which may be reduced average opioid consumption, and in some embodiments reduced average daily opioid consumption. In some embodiments, the treatment improves cancer pain measures compared to treatment with an opioid analgesic. In some embodiments, the treatment improves cancer pain measures compared to treatment with morphine.
In some embodiments the treatment effectively improves the cancer pain for at least 24 weeks, 32 weeks, 40 weeks, 48 weeks, or 56 weeks after start of treatment.
In some embodiments, the treatment provides 10%, 15%, 20%, 25%, 30%, 35% of patients with at least 30%, 50%, 70% or 90% improvement in cancer pain. In some embodiments, the treatment provides at least 20% of patients with at least 50% improvement in cancer pain at week 8 after start of treatment.
In some embodiments the patient has a history of inadequate pain relief from or intolerance to prior therapy including analgesic therapy. The prior therapy can comprise at least agents used for treatment of cancer pain. These agents can include acetaminophen/low-dose NSAIDs; prescription NSAIDs; opioids; tapentadol; tricyclic antidepressants; benzodiazepines or skeletal muscle relaxants; lidocaine patch; and/or duloxetine or other serotonin-norepinephrine reuptake inhibitors.
In some embodiments, the patient was previously treated with the analgesic therapy prior to administering tanezumab. In some embodiments the patient continues to receive analgesic therapy during treatment with tanezumab. The analgesic therapy may be the same as the analgesic therapy prior to administering tanezumab.
In some embodiments, the patient has a history of treatment with at least one, at least two, at least three, at least four or at least five prior therapies. The prior therapies may be from the same or different class of agent for treatment of cancer pain.
In some embodiments, the patient experiences some benefit from the analgesic therapy, but still requires additional pain relief. For example, despite experiencing some benefit from an analgesic therapy, the patient continues to experience cancer pain, which may be determined by an average pain score of at least 5 for the index cancer pain site; a baseline Patient’s Global Assessment of cancer pain of “fair”, “poor” or “very poor”; or an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
In some embodiments, the analgesic therapy comprises the administration of an opioid to the patient. In some embodiments the analgesic therapy comprises the administration of morphine to the patient.
In some embodiments, the treatment averts opioid addiction in the patient. In some embodiments, the treatment avoids administration of an opioid and averts opioid addiction.
In some embodiments the patient has a history of addiction to analgesics. In some embodiments, the patient has a history of addiction to opioids. In some embodiments, the patient has a history of addiction to morphine or tramadol.
In some embodiments, the analgesic may be selected from opioids, NSAIDs, acetaminophen. In some embodiments, the NSAID is selected from ibuprofen, naproxen, naprosyn, diclofenac, ketoprofen, tolmetin, slindac, mefenamic acid, meclofenamic acid, diflunisal, flufenisal, piroxim, sudoxicam, isoxicam; a COX-2 inhibitor selected from celecoxib, rofecoxib, DUP-697, flosulide, meloxicam, 6-methoxy-2 naphthylacetic acid, MK-966, nabumetone, nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof. In some embodiments, the opioid may be any compound exhibiting morphine like biological activity. In some embodiments, the opioid analgesic is selected from: tramadol, morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or combinations thereof.
In some embodiments, the patient is not administered an NSAID during the treatment with tanezumab. In some embodiments, the patient is not administered concomitant NSAID during the treatment with tanezumab. In some embodiments the patient is not administered an NSAID for any more than 10 days in an eight-week treatment interval. In some embodiments, the patient is not administered an NSAID for 16 weeks after the last dose of tanezumab.
In some embodiments, the patient is not administered a placebo which may be an oral placebo. In some embodiments, the patient has moderate to severe cancer pain which may be predominantly due to bone metastasis.
In some embodiments, the patient has an average pain score of greater than 5 at the index cancer site. In some embodiments, the patient has an average pain score of about 6 at the index cancer pain site. In some embodiments, the patient has an average pain score of about 7 at the index cancer pain site.
In some embodiments, the patient has an average pain score of greater than 5 at the index cancer pain site and/or has a total weekly opioid use of less than 150, 125, 100, or 75 morphine equivalents. In some embodiments, the patient has a total weekly opioid use of less than or equal to 100 morphine equivalents. In some embodiments, the patient has a total weekly opioid use of less than or equal to 99, 98, 97, 96, 95 mg of morphine equivalence. In some embodiments, the patient has a total weekly opioid use of less than or equal to 70, 65, 60, 55 or 50 morphine equivalents. In some embodiments, the patient has a total weekly opioid use of less than or equal to 60.5 morphine equivalents.
In some embodiments the patient has had cancer pain for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 or at least 12 months prior to treatment with tanezumab. In one embodiment, the patient has had cancer pain for at least 3 months. In some embodiments, the patent has had cancer pain for at least 18, 24, 30, 36, 42, 48 or 56 months prior to treatment with tanezumab.
In some embodiments, the cancer pain is from cancer originated in bone. In some embodiments, the cancer pain is from osteosarcoma. In some embodiments, the cancer pain is from cancer metastasized to bone (i.e., bone metastasis). In some embodiments, the bone metastasis is prostate cancer metastasized to bone. In some embodiments, the bone metastasis is breast cancer metastasized to bone. In some embodiments, the bone metastasis is lung cancer metastasized to bone. In some embodiments, the bone metastasis is sarcoma metastasized to bone. In some embodiments, the bone metastasis is kidney cancer metastasized to bone. In some embodiments, the bone metastasis is multiple myeloma metastasized to bone. In some embodiments, the cancer pain is from cancer other than breast cancer, prostate cancer or lung cancer metastasized to bone. In some embodiments, the tumor is less aggressive as assessed by ECOG Performance Status Score prior to or at start of treatment. In some embodiments the ECOG Performance Status Score is less than or equal to 1 prior to or at start of treatment. In some embodiments, the patient does not receive concomitant anti-cancer therapy.
In some embodiments, tanezumab is administered for at least two, three, four, five, six or more doses at eight weekly intervals. In some embodiments, tanezumab is administered to the patient for at least 16, 24, 32, 40, 48, 56, 56, 72, 80, 88 or 96 weeks. In some embodiments, tanezumab is administered to the patient for at least 16 weeks. In some embodiments tanezumab is administered to the patient for at least 24 weeks. In some embodiments tanezumab is administered to the patient for at least 48 weeks.
In some embodiments, the patient prior to treatment with tanezumab does not have osteoarthritis and/or pain associated with osteoarthritis.
In some embodiments, the patient prior to treatment with tanezumab has no or possible radiographic evidence of hip osteoarthritis (Kellgren Lawrence Grade <1) and/or does not meet the American College of Rheumatology (ACR) clinical and radiographic criteria; and/or does not have pain associated with hip osteoarthritis.
In some embodiments, the patient prior to treating with tanezumab has no symptoms and radiographic evidence of osteoarthritis of the shoulder.
In some embodiments, the patient is subjected to radiographic assessment of the knee, hip and/or shoulder prior to starting treatment with tanezumab. In some embodiments, if radiographic assessment identified rapidly progressive osteoarthritis of the joint, the patient is excluded from the treatment.
In some embodiments, the method further comprises conducting a radiographic assessment of the knee, hip and/or shoulder at regular intervals during treatment.
In some embodiments, a patient may be excluded from treatment, before or during treatment, if the patient has been diagnosed as having osteoarthritis of the knee or hip as defined by the American College of Rheumatology (ACR) clinical and radiographic criteria; having Kellgren-Lawrence Grade >2 radiographic evidence of hip osteoarthritis; and/or having Kellgren-Lawrence Grade >3 radiographic assessment of knee osteoarthritis and/or having symptoms and radiographic evidence of osteoarthritis of the shoulder.
In some embodiments, a patient may be excluded from treatment, before or during treatment, if there is radiographic evidence of any of the following conditions as determined by the central radiology reviewer and as defined in an imaging atlas at screening: 1) rapidly progressive osteoarthritis, 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
In some embodiments, a patient may be excluded from treatment, before or during treatment, if there is radiographic evidence of any of the following conditions in any screening radiograph as determined by a central radiology reviewer and as defined in an imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; other arthropathies (e.g., rheumatoid arthritis), systemic metabolic bone disease (e.g., pseudogout, Paget’s disease; metastatic calcifications), large cystic lesions, stress or traumatic fracture.
In some embodiments, patients not having satisfactory clinical response after receiving two doses do not receive further doses.
In some embodiments, the method further comprises administering an effective amount of a second therapeutic agent. In some embodiments, tanezumab may be administered in conjunction with other therapies for bone cancer, such as radiation, and chemotherapy. Tanezumab may also be administered in conjunction with other analgesics used for cancer pain. The amount of these analgesics administered for cancer pain alleviation may be reduced, comparing to the amount administered in the absence of tanezumab. Adverse effects due to these analgesics may be reduced or eliminated when they are co-administered with tanezumab.
In some embodiments, prior to treatment with tanezumab, the patient has one or more of a) cancer pain from cancer other than from breast cancer, prostate cancer or lung cancer metastasized to bone; b) an average pain score of about 6 at the index cancer pain site; c) a total weekly median opioid use of less than about 100 morphine equivalents; d) a tumor that is less aggressive as assessed by ECOG Performance Status Score; and e) no concomitant anti-cancer therapy. In some embodiments, the patient has two or more, three or more, four or more, or all of these characteristics.
In some embodiments, the patient has a tumor that is less aggressive having a ECOG Performance Status Score of less than or equal to 1. In some embodiments, the patient does not have a tumor having a ECOG Performance Status Score of 2 or more. An ECOG Performance Status Score of 2 or more is indiciative of a more aggressive tumor. Also provided is tanezumab for use in a method of treating cancer pain as described herein. Also provided is the use of tanezumab in the manufacture of a medicament for use in a method for treating cancer pain as described herein.
In embodiments that refer to a method of treating cancer pain as described herein, such embodiments are also further embodiments of tanezumab for use in that treatment, or alternatively of the use of tanezumab in the manufacture of a medicament for use in that treatment.
Preferred features of each aspect of the invention apply equally to each other aspect mutatis mutandis.
Brief Description of the Fiqures/Drawinqs
Figure 1 is a study outline for the study described in Example 1.
Figure 2 shows the change from baseline for daily average pain intensity at the index cancer pain site up to week 8.
Figure 3 shows the change from baseline for daily average pain intensity at the index cancer pain site up to week 24.
Figure 4 shows the change in average daily pain intensity at the index cancer pain site up to week 8.
Figure 5 shows the change from baseline for daily average pain intensity at the index cancer pain site up to day 7.
Figure 6 shows response rates for daily average pain intensity at index cancer pain site at week 8.
Figure 7 shows >50% response rates over time in daily average pain intensity at index cancer pain site.
Figure 8 shows change from baseline for daily worst pain intensity at the index cancer pain site up to week 24.
Figure 9 shows average daily pain at index cancer pain site change from baseline to week 8 by primary cancer.
Figure 10 shows average daily pain at index cancer pain site change from baseline to week 8 by geographical region.
Figure 11 shows average daily pain at index cancer pain site change from baseline to week 8 by median pain score at baseline (score of 6). Figure 12 shows average daily pain at index cancer pain site change from baseline to week 8 by median opioid use at baseline (96 mg morphine equivalence).
Figure 13 shows average daily pain at index cancer pain site change from baseline to week 8 by tumor aggressiveness.
Figure 14 shows average daily pain at index cancer pain site change from baseline to week 8 by concomitant anticancer therapy.
Detailed Description
The invention disclosed herein is directed to treatment of cancer pain predominantly due to bone metastases in patients receiving background opioid therapy.
Accordingly, in one aspect, the invention provides a method of treating cancer pain in a patient in need thereof, the method comprising administering 20 mg of tanezumab subcutaneously to the patient, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis, cancer originated in bone, or multiple myeloma, and wherein the patient has had inadequate pain relief with opioid analgesics.
In some embodiments, the patient has: i. an average Pain Score of at least 5 for the index cancer pain site; ii. a Patient's Global Assessment of Cancer Pain of "fair", "poor" or "very poor"; iii. an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1, or 2; and iv. no joint safety event selected from: 1) rapidly progressive osteoarthritis (type 1 or type 2), 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fracture, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
General Techniques
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Flarbor Press; Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Flumana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.l. Freshney, ed, 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995).
Definitions
The following terms, unless otherwise indicated, shall be understood to have the following meanings:
An “antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site. Antigen binding portions include, for example, Fab, Fab’, F(ab , Fd, Fv, domain antibodies (dAbs, e.g., shark and camelid antibodies), fragments including complementarity determining regions (CDRs), single chain variable fragment antibodies (scFv), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, lgG3, lgG4, IgAi and lgA2. The heavy- chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity determining regions (CDRs) also known as hypervariable regions, and contribute to the formation of the antigen binding site of antibodies. If variants of a subject variable region are desired, particularly with substitution in amino acid residues outside of a CDR region (i.e., in the framework region), appropriate amino acid substitution, preferably, conservative amino acid substitution, can be identified by comparing the subject variable region to the variable regions of other antibodies which contain CDR1 and CDR2 sequences in the same canonical class as the subject variable region (Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987).
In certain embodiments, definitive delineation of a CDR and identification of residues comprising the binding site of an antibody is accomplished by solving the structure of the antibody and/or solving the structure of the antibody-ligand complex. In certain embodiments, that can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, and the conformational definition.
The Kabat definition is a standard for numbering the residues in an antibody and is typically used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account positions of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83. The AbM definition uses an integrated suite of computer programs produced by Oxford Molecular Group that model antibody structure. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; “AbM™, A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from primary sequence using a combination of knowledge databases and ab initio methods, such as those described by Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. The contact definition is based on an analysis of the available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined in accordance with any of Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.
As known in the art, a “constant region” of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.
As used herein, "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or may be made by recombinant DNA methods such as described in U.S. Pat. No. 4,816,567. The monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCaffertyetal., 1990, Nature 348:552-554, for example.
As used herein, "humanized" antibody refers to forms of non-human (e.g. murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin. Preferably, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. The humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance.
In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may include residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. In general, the humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will include at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. In some aspects of the invention the antibodies have Fc regions modified as described in PCT International Publication No. WO 99/58572. Other forms of humanized antibodies have one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H 1 , CDR H2, or CDR H3) which may be altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody.
Humanization can be essentially performed following the method of Winter and co-workers (Jones et al. Nature 321:522-525 (1986); Riechmann et al. Nature 332:323- 327 (1988); Verhoeyen et al. Science 239:1534-1536 (1988)), by substituting rodent or mutant rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. See also U.S. Patent Nos. 5,225,539; 5,585,089; 5,693,761 ; 5,693,762; 5,859,205; which are incorporated herein by reference in its entirety. In some instances, residues within the framework regions of one or more variable regions of the human immunoglobulin are replaced by corresponding non-human residues (see, for example, U.S. Patent. Nos. 5,585,089; 5,693,761; 5,693,762; and 6,180,370). Furthermore, humanized antibodies may include residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance (e.g., to obtain desired affinity). In general, the humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will include at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details see Jones et al. Nature 321 :522-525 (1986); Riechmann et al. Nature 332:323-327(1988); and Presta Curr. Op. Struct. Biol. 2:593- 596 (1992); which are incorporated herein by reference in its entirety. Accordingly, such “humanized” antibodies may include antibodies wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some framework residues are substituted by residues from analogous sites in rodent antibodies. See, for example, U.S. Patent Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205. See also U.S. Patent No. 6,180,370, and PCT International Publication No. WO 01/27160, where humanized antibodies and techniques for producing humanized antibodies having improved affinity for a predetermined antigen are disclosed.
A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen binding residues.
The term “chimeric antibody” is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
The antibody “tanezumab” is a humanized immunoglobulin G Type 2 (lgG2) monoclonal antibody directed against human nerve growth factor (NGF). Tanezumab binds to human NGF with high affinity and specificity, and blocks the activity of NGF effectively in cell culture models. Tanezumab and/or its murine precursor have been shown to be an effective analgesic in animal models of pathological pain including arthritis, cancer pain, and post-surgical pain. Tanezumab has the sequences for the variable heavy chain region and variable light chain region of SEQ ID NOs: 1 and 2, respectively. The heavy chain and light chain sequences are provided in SEQ ID NO: 9 and 10, or SEQ ID NOs: 11 and 10. The C-terminal lysine (K) of the heavy chain amino acid sequence of SEQ ID NO: 9 is optional and may be processed, resulting in a heavy chain amino acid sequence lacking the C-terminal lysine (K) and having the sequence shown in SEQ ID NO: 11. Sequences of tanezumab are provided in Table 1 below. Tanezumab is described, as antibody E3, in W02004058184, herein incorporated by reference.
As known in the art, “polynucleotide,” or “nucleic acid,” as used interchangeably herein, refer to chains of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the chain. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L- lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5’ and 3’ terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2’-0-methyl-, 2’-0-allyl, 2’-fluoro- or 2’-azido-ribose, carbocyclic sugar analogs, alpha- or beta-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(0)S(“thioate”), P(S)S (“dithioate”), (0)NR2 (“amidate”), P(0)R, P(0)OR’, CO or CH2 (“formacetal”), in which each R or R’ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.
An antibody that “preferentially binds” or “specifically binds” (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a target (e.g., PD-1) epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other target epitopes or non-target epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target mayor may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.
As used herein, “substantially pure” refers to material which is at least 50% pure (i.e., free from contaminants), more preferably, at least 90% pure, more preferably, at least 95% pure, yet more preferably, at least 98% pure, and most preferably, at least 99% pure.
A “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this invention.
As known in the art, the term "Fc region" is used to define a C-terminal region of an immunoglobulin heavy chain. The "Fc region" may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The numbering of the residues in the Fc region is that of the EU index as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3. As is known in the art, an Fc region can be present in dimer or monomeric form.
As used in the art, "Fc receptor" and “FcR” describe a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. FcRs are reviewed in Ravetch and Kinet, 1991, Ann. Rev. Immunol., 9:457-92; Capel et al., 1994, Immunomethods, 4:25-34; and de Flaas et al., 1995, J. Lab. Clin. Med., 126:330-41. “FcR” also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyeret al., 1976, J. Immunol., 117:587; and Kim et al., 1994, J. Immunol., 24:249).
The term “compete”, as used herein with regard to an antibody, means that a first antibody, or an antigen-binding portion thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or an antigen-binding portion thereof, such that the result of binding of the first antibody with its cognate epitope is detectably decreased in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. The alternative, where the binding of the second antibody to its epitope is also detectably decreased in the presence of the first antibody, can, but need not be the case. That is, a first antibody can inhibit the binding of a second antibody to its epitope without that second antibody inhibiting the binding of the first antibody to its respective epitope. Flowever, where each antibody detectably inhibits the binding of the other antibody with its cognate epitope or ligand, whether to the same, greater, or lesser extent, the antibodies are said to “cross-corn pete” with each other for binding of their respective epitope(s). Both competing and cross- competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate, based upon the teachings provided herein, that such competing and/or cross-competing antibodies are encompassed and can be useful for the methods disclosed herein.
A “functional Fc region” possesses at least one effector function of a native sequence Fc region. Exemplary “effector functions” include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity; phagocytosis; down-regulation of cell surface receptors (e.g. B cell receptor), etc. Such effectorfunctions generally require the Fc region to be combined with a binding domain (e.g. an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions.
A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effectorfunction of the native sequence Fc region. Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% sequence identity with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably, at least about 90% sequence identity therewith, more preferably, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity therewith.
As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include reduction or improvement in cancer pain, for example as compared to before administration of tanezumab.
“Ameliorating” means a lessening or improvement of cancer pain, for example as compared to not administering tanezumab as described herein. “Ameliorating” also includes shortening or reduction in duration of a symptom.
As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired results. In more specific aspects, an effective amount prevents, alleviates or ameliorates cancer pain. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing cancer pain, decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, and/or delaying the progression of the disease in patients. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
The term “inadequate treatment response to prior therapy” refers to a patient who has experienced an adverse event after treatment with the prior therapy; who is refractory to treatment with the prior therapy; who shows no clinically meaningful improvement in one or more measures of cancer pain with prior therapy; who experiences some benefit from prior therapy but still requires additional pain relief; who is addicted to the prior therapy (including analgesics such as opioids); and/or who is unwilling to take the prior therapy. In some embodiments, the patient has a history of inadequate pain relief from or intolerance to prior therapy, which may comprise at least three different classes of analgesics.
Treatment “effectively improves” or “effectively reduces” when assessment of the cancer pain is quantified via a clinical measure relative to baseline and during and/or after the treatment period. The difference between the clinical measure at baseline and during/after treatment is compared and used to determine whether the cancer pain has improved, and the treatment is effective. This comparison can include comparison to placebo or to one or more of the prior therapies. In one embodiment, the comparison can be to placebo or to treatment with an opioid analgesic, such as morphine or tramadol; or a NSAID, such as celecoxib. The clinical measure can be average daily pain intensity. The average daily pain intensity measure can be determined for the patient at baseline and then determined throughout the treatment period, such as at weeks 2, 4, 6, 8, 16, 24, 32, 40, 48, 56, or longer. Similarly, the worst daily pain intensity can also be determined in this manner. Yet further, the Patient Global Assessment (PGA) of cancer pain measure can also be determined in this manner.
In some embodiments, the treatment provides 10%, 15%, 20%, 25%, 30%, 35% of patients with at least 30%, 50%, 70% or 90% improvement in cancer pain. In some embodiments, the treatment provides at least 20% of patients with at least 50% improvement in cancer pain at week 8 after start of treatment.
The term “baseline” refers to a value of a cancer pain associated measure for a patient prior to administration of tanezumab as part of the treatment method. In some embodiments, the term “baseline” refers to a value of a sign or symptom associated measure for control healthy subjects that do not have cancer pain.
In some embodiments, treatment with tanezumab effectively improves cancer pain at at least 8 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 10 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 12 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 14 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 16 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 24 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 32 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 40 weeks after start of treatment with the antibody. In some embodiments, treatment effectively improves cancer pain at at least 56 weeks after start of treatment with the antibody.
In some embodiments, the cancer pain is moderate to severe.
Average pain and worst pain in the index bone metastasis cancer pain site, non index cancer pain sites and average pain in painful major joints can be assessed by the subject at approximately the same time each day (or each week) with an 11 -point Numeric Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain). The subjects should describe their pain in the painful site during the past 24 hours by choosing the appropriate number from 0 to 10.
The most painful site of bone metastasis is considered the index bone metastasis cancer pain site (interchangeably referred to as “index cancer pain site”). Subjects record daily pain ratings for the index bone metastasis cancer pain site.
The Patient Global Assessment (PGA) measure is a global evaluation that utilizes a 5-point Likert scale with a score of 1 being best (very good) and a score of 5 being worst (very poor). Functional assessment tools based on performance, such as the Eastern Cooperative Oncology Group (ECOG) Performance Status (Oken MM, Creech RH, Tormey DC, et al. Am J Clinical Oncology 1982; 5(6):649-55) are validated and widely used tools in cancer care. The ECOG Performance Status instrument is rated on a 5- point scale, with lower scores representing higher functional status.
Kellgren-Lawrence x-ray grade is a method of classifying the severity of osteoarthritis (Kellgren and Lawrence., Ann Rheum Dis 2000: 16(4): 494-502).
The American College of Rheumatology (ACR) classification criteria for osteoarthritis (Altman, et al. Arthritis Rheum 1986; 29:1039-49) includes clinical and radiographic criteria for osteoarthritis of the hip or knee.
Rapidly progressive osteoarthritis (RPOA) of the hip was first described by Forestier in 1957 and subsequently described in a number of studies as atrophic osteoarthritis, rapidly destructive osteoarthritis, rapidly destructive arthropathy, rapidly progressive hip disease, or rapidly destructive coxarthrosis. Rapidly progressive hip osteoarthritis is characterized by subjects who typically present with hip pain, often severe, with radiographs that show rapid joint space narrowing as a result of chrondrolysis from a prior radiograph and, subsequently, an osteolytic phase with severe progressive atrophic bone destruction involving the femoral head and the acetabulum. There can be marked flattening of the femoral head and loss of subchondral bone in the weight bearing area and, in some cases, the femoral head appears sheared off. Osteophytes are typically conspicuously small or absent. Bone sclerosis is often present at sites of impaction of the femoral head and the acetabulum, subchondral detritus is invariably present and bone fragmentation and debris are commonly observed that can lead to synovitis. Lequesne proposed that subjects with 2 mm/year or greater of joint space narrowing or loss of more than 50% of the joint space within 1 year should be considered to have rapidly progressive osteoarthritis. Due to a lack of longitudinal studies, it is not clear what proportion of subjects with rapid loss of joint space (chondrolysis) will progress to have bone destruction. Rapid progression of osteoarthritis has also been described in the shoulder and the knee.
Radiographic assessments (x-rays) of both knees, both hips and both shoulders can be performed or obtained prior to treatment, at screening. Other major joints exhibiting signs or symptoms suggestive of osteoarthritis may also be imaged. A major joint is defined as a mobile synovial joint in the limbs such as shoulders, elbows, wrists, hips, knees, ankles and excluding the joints of the toes and hands. Any joint imaged at Screening or other at risk joints identified during the study period should also be imaged.
A central radiology reader (Central Reader) may review the radiology images for assessment of eligibility including determination and identification of exclusionary joint conditions. Radiographs required at screening may be obtained at least two weeks and up to 32 days prior to the beginning of the Baseline Assessment Period (BAP) to permit central radiology review of the images and to establish subject eligibility for initial dosing with tanezumab. In some embodiments, subjects may not be permitted to start dosing with tanezumab until the screening radiographs are reviewed and eligibility is established.
The X-ray technologists, in addition to their professional training and certifications, are trained in performing the radiographic protocols for the knees, hips, and shoulders. To facilitate reproducibility and accuracy of joint space width measurement in the knees and hips, a semi -automated software and positioning frame standardized subject and joint positioning protocol can be utilized. The Core Imaging Laboratory may be responsible for working with the sites to ensure quality, standardization and reproducibility of the radiographic images/assessments made at the Screening and follow-up time-points. Additional details regarding the required X-rays may be provided in a site imaging manual.
Central radiology readers (Central Readers) may be board certified radiologists or have the international equivalent as musculoskeletal radiologists. The Central Readers may be governed by an imaging atlas and an imaging Charter which includes a specific description of the scope of their responsibilities. Central Readers may review the radiology images at Screening for assessment of eligibility (including determination of Kellgren-Lawrence Grade) and identification of exclusionary joint conditions such as rapidly progressive osteoarthritis, atrophic or hypotrophic osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis and pathological fractures. After start of treatment, the Central Reader may review radiology images for diagnosis of joint conditions that would warrant further evaluation by the Adjudication Committee such as possible or probable rapidly progressive osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis or pathological fracture.
For subjects who are identified with a possible or probable joint event (i.e., rapidly progressive osteoarthritis, subchondral insufficiency fractures, spontaneous osteonecrosis of the knee (SPONK), primary osteonecrosis or pathological fracture) and subjects undergoing total joint replacement for any reason, all images and other source documentation may be provided to the blinded Adjudication Committee for review and adjudication of the event. The Adjudication Committee’s assessment of the event may represent the final classification of the event.
Patients may be excluded from treatment with tanezumab, during or before treatment with tanezumab, if there is radiographic evidence of any of the following conditions in any screening radiograph as determined by a central radiology reviewer and as defined in an imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; other arthropathies (e.g., rheumatoid arthritis), systemic metabolic bone disease (e.g., pseudogout, Paget’s disease; metastatic calcifications), large cystic lesions, primary or metastatic tumor lesions, stress or traumatic fracture. In some embodiments a patient may be excluded from treatment with tanezumab, before or during the treatment with tanezumab, if there is radiographic evidence of any of the following conditions as determined by the central radiology reviewer and as defined in an imaging atlas at screening: 1) rapidly progressive osteoarthritis, 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
In some embodiments a patient may be excluded from treatment, before or during treatment, with tanezumab if the patient has been diagnosed as having osteoarthritis of the knee or hip as defined by the American College of Rheumatology (ACR) clinical and radiographic criteria; having Kellgren-Lawrence Grade >2 radiographic evidence of hip osteoarthritis; and/or having Kellgren-Lawrence Grade >3 radiographic assessment of knee osteoarthritis and/or having symptoms and radiographic evidence of osteoarthritis of the shoulder. The radiographic criteria may be assessed by a Central Reader.
In some embodiments, a patient may be included for treatment with tanezumab according to the invention if the patient has one or more of a) cancer pain from cancer other than from breast cancer, prostate cancer or lung cancer metastasized to bone; b) an average pain score of about 6 at the index cancer pain site; c) a total weekly median opioid use of less than about 100 morphine equivalents; d) a tumor that is less aggressive as assessed by ECOG Performance Status (which may be less than or equal to 1); and e) no concomitant anti-cancer therapy. In some embodiments the patient has two or more, three or more, four or more, or all of these characteristics. A “patient”, an “individual” or a "subject", used interchangeably herein, is a mammal, more preferably, a human. Mammals also include, but are not limited to, farm animals (e.g., cows, pigs, horses, chickens, etc.), sport animals, pets, primates, horses, dogs, cats, mice and rats.
As used herein, "vector" means a construct, which is capable of delivering, and, preferably, expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.
As used herein, "expression control sequence" means a nucleic acid sequence that directs transcription of a nucleic acid. An expression control sequence can be a promoter, such as a constitutive or an inducible promoter, or an enhancer. The expression control sequence is operably linked to the nucleic acid sequence to be transcribed.
As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).
The term “effector function” refers to the biological activities attributable to the Fc region of an antibody. Examples of antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), Fc receptor binding, complement dependent cytotoxicity (CDC), phagocytosis, C1q binding, and down regulation of cell surface receptors (e.g., B cell receptor; BCR). See, e.g., U.S. Pat No. 6,737,056. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions. An exemplary measurement of effector function is through Fcy3 and/or C1q binding.
As used herein “antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g. natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC activity of a molecule of interest can be assessed using an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or 5,821,337. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., 1998, PNAS (USA), 95:652- 656.
“Complement dependent cytotoxicity” or “CDC” refers to the lysing of a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g. an antibody) complexed with a cognate antigen. To assess complement activation, a CDC assay, e.g. as described in Gazzano-Santoro et al., J. Immunol. Methods, 202: 163 (1996), may be performed.
The term "kon" or “ka”, as used herein, refers to the rate constant for association of an antibody to an antigen. Specifically, the rate constants (kon or ka and koff or kd) and equilibrium dissociation constants are measured using whole antibody (i.e. bivalent) and monomeric proteins.
The term "koff" or “kd”, as used herein, refers to the rate constant for dissociation of an antibody from the antibody/antigen complex.
The term "KD", as used herein, refers to the equilibrium dissociation constant of an antibody-antigen interaction.
Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.” Numeric ranges are inclusive of the numbers defining the range. Generally speaking, the term “about” refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g. within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater. Where the term “about” is used within the context of a time period (years, months, weeks, days etc.), the term “about” means that period of time plus or minus one amount of the next subordinate time period (e.g. about 1 year means 11-13 months; about 6 months means 6 months plus or minus 1 week; about 1 week means 6-8 days; etc.), or within 10 per cent of the indicated value, whichever is greater.
The term “subcutaneous administration” refers to the administration of a substance into the subcutaneous layer.
The term “preventing” or “prevent” refers to (a) keeping a disorder from occurring or (b) delaying the onset of a disorder or onset of symptoms of a disorder.
It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of” and/or “consisting essentially of” are also provided.
Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise," or variations such as "comprises" or "comprising" will be understood to imply the inclusion of astated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.
Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The materials, methods, and examples are illustrative only and not intended to be limiting. Tanezumab
Provided herein is tanezumab for use in the methods of treatment as described herein.
Tanezumab is a humanized immunoglobulin G Type 2 (lgG2) monoclonal antibody, derived from a murine precursor with a mutation in the Fc portion of the antibody to decrease its ability to activate complement or to support antibody dependent cell- mediated cytotoxicity. Tanezumab is highly potent in sequestering NGF and preventing interaction with the trkA or p75 receptors.
Exemplary antibody sequences for tanezumab include, but are not limited to, the sequences listed below.
Table 1
Figure imgf000033_0001
Figure imgf000034_0001
[* C-terminal lysine (K) of the heavy chain amino acid sequence of SEQ ID NO: 9 is optional]
The antibodies as described herein can be made by any method known in the art. An antibody may be made recombinantly using a suitable host cell. A nucleic acid encoding an anti-NGF antibody of the present disclosure can be cloned into an expression vector, which can then be introduced into a host cell, where the cell does not otherwise produce an immunoglobulin protein, to obtain the synthesis of an antibody in the recombinant host cell. Any host cell susceptible to cell culture, and to expression of protein or polypeptides, may be utilized in accordance with the present invention. In certain embodiments, the host cell is mammalian. Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). Nonlimiting exemplary mammalian cells include, but are not limited to, NS0 cells, HEK 293 and Chinese hamster ovary (CHO) cells, and their derivatives, such as 293-6E and CHO DG44 cells, CHO DXB11, and Potelligent® CHOK1SV cells (BioWa/Lonza, Allendale, NJ). Mammalian host cells also include, but are not limited to, human cervical carcinoma cells (HeLa, ATCC CCL 2), baby hamster kidney (BHK, ATCC CCL 10) cells, monkey kidney cells (COS), and human hepatocellular carcinoma cells (e.g., Hep G2). Other non-limiting examples of mammalian cells that may be used in accordance with the present invention include human retinoblasts (PER.C6®; CruCell, Leiden, The Netherlands); monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line 293 (HEK 293) or 293 cells subcloned for growth in suspension culture (Graham et al., J. Gen Virol. 1997; 36:59); mouse sertoli cells (TM4, Mather, Biol. Reprod. 1980; 23:243-251); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1 587); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TR1 cells (Mather et al., Annals N.Y. Acad. Sci. 1982; 383:44-68); MRC 5 cells; FS4 cells; a human hepatoma line (Hep G2); and numerous myeloma cell lines, including, but not limited to, BALB/c mouse myeloma line (NS0/1, ECACC No: 85110503), NS0 cells and Sp2/0 cells.
Additionally, any number of commercially and non-commercially available cell lines that express polypeptides or proteins may be utilized. One skilled in the art will appreciate that different cell lines might have different nutrition requirements and/or might require different culture conditions for optimal growth and polypeptide or protein expression and will be able to modify conditions as needed. For the production of hybridoma cell lines, the route and schedule of immunization of the host animal are generally in keeping with established and conventional techniques for antibody stimulation and production, as further described herein. General techniques for production of human and mouse antibodies are known in the art and/or are described herein.
It is contemplated that any mammalian subject including humans or antibody producing cells therefrom can be manipulated to serve as the basis for production of mammalian, including human and hybridoma cell lines. Typically, the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantar, and/or intradermally with an amount of immunogen, including as described herein.
Hybridomas can be prepared from the lymphocytes and immortalized myeloma cells using the general somatic cell hybridization technique of Kohler, B. and Milstein, C., Nature 256:495-497, 1975 or as modified by Buck, D. W., et al., In Vitro, 18:377-381 , 1982. Available myeloma lines, including but not limited to X63-Ag8.653 and those from the Salk Institute, Cell Distribution Center, San Diego, Calif., USA, may be used in the hybridization. Generally, the technique involves fusing myeloma cells and lymphoid cells using a fusogen such as polyethylene glycol, or by electrical means well known to those skilled in the art. After the fusion, the cells are separated from the fusion medium and grown in a selective growth medium, such as hypoxanthine-aminopterin-thymidine (HAT) medium, to eliminate unhybridized parent cells. Any of the media described herein, supplemented with or without serum, can be used for culturing hybridomas that secrete monoclonal antibodies. As another alternative to the cell fusion technique, EBV immortalized B cells may be used to produce the monoclonal antibodies of the subject invention. The hybridomas are expanded and subcloned, if desired, and supernatants are assayed for anti-immunogen activity by conventional immunoassay procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay).
Hybridomas that may be used as source of antibodies encompass all derivatives, progeny cells of the parent hybridomas that produce monoclonal antibodies.
Hybridomas that produce antibodies used for the present invention may be grown in vitro or in vivo using known procedures. The monoclonal antibodies may be isolated from the culture media or body fluids, by conventional immunoglobulin purification procedures such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration, if desired. Undesired activity, if present, can be removed, for example, by running the preparation over adsorbents made of the immunogen attached to a solid phase and eluting or releasing the desired antibodies off the immunogen. Immunization of a host animal with cells expressing the antibody target (e.g., PD-1), a human target protein (e.g., PD-1), or a fragment containing the target amino acid sequence conjugated to a protein that is immunogenic in the species to be immunized, e.g., keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor using a bifunctional or derivatizing agent, for example, maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine residues), N- hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride, SOCI2, or R1N=C=NR, where R and R1 are different alkyl groups, can yield a population of antibodies (e.g., monoclonal antibodies).
If desired, the antibody (monoclonal or polyclonal) of interest may be sequenced and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest may be maintained in vector in a host cell and the host cell can then be expanded and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be carried out through cloning of antibody genes from B cells by means known in the art. See, e.g. Tiller et al., J. Immunol. Methods 329, 112, 2008; U.S. Pat. No. 7,314,622.
In some embodiments, antibodies may be made using hybridoma technology. It is contemplated that any mammalian subject including humans or antibody producing cells therefrom can be manipulated to serve as the basis for production of mammalian, including human, hybridoma cell lines. The route and schedule of immunization of the host animal are generally in keeping with established and conventional techniques for antibody stimulation and production, as further described herein. Typically, the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantar, and/or intradermally with an amount of immunogen, including as described herein.
In some embodiments, antibodies as described herein are glycosylated at conserved positions in their constant regions (Jefferis and Lund, 1997, Chem. Immunol. 65:111-128; Wright and Morrison, 1997, TibTECH 15:26-32). The oligosaccharide side chains of the immunoglobulins affect the protein’s function (Boyd et al., 1996, Mol. Immunol. 32:1311-1318; Wittwe and Howard, 1990, Biochem. 29:4175-4180) and the intramolecular interaction between portions of the glycoprotein, which can affect the conformation and presented three-dimensional surface of the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, 1996, Current Opin. Biotech. 7:409-416). Oligosaccharides may also serve to target a given glycoprotein to certain molecules based upon specific recognition structures. Glycosylation of antibodies has also been reported to affect antibody-dependent cellular cytotoxicity (ADCC). In particular, antibodies produced by CHO cells with tetracycline-regulated expression of b(1,4)-N- acetylglucosaminyltransf erase III (GnTIII), a glycosyltransf erase catalyzing formation of bisecting GlcNAc, was reported to have improved ADCC activity (Umana et al., 1999, Nature Biotech. 17:176-180).
Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above- described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).
The glycosylation pattern of antibodies may also be altered without altering the underlying nucleotide sequence. Glycosylation largely depends on the host cell used to express the antibody. Since the cell type used for expression of recombinant glycoproteins, e.g. antibodies, as potential therapeutics is rarely the native cell, variations in the glycosylation pattern of the antibodies can be expected (see, e.g. Hse et al., 1997, J. Biol. Chem. 272:9062-9070).
In addition to the choice of host cells, factors that affect glycosylation during recombinant production of antibodies include growth mode, media formulation, culture density, oxygenation, pH, purification schemes and the like. Various methods have been proposed to alter the glycosylation pattern achieved in a particular host organism including introducing or overexpressing certain enzymes involved in oligosaccharide production (U.S. Patent Nos. 5,047,335; 5,510,261 and 5,278,299). Glycosylation, or certain types of glycosylation, can be enzymatically removed from the glycoprotein, for example, using endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, endoglycosidase F3. In addition, the recombinant host cell can be genetically engineered to be defective in processing certain types of polysaccharides. These and similar techniques are well known in the art.
Other methods of modification include using coupling techniques known in the art, including, but not limited to, enzymatic means, oxidative substitution and chelation. Modifications can be used, for example, for attachment of labels for immunoassay. Modified polypeptides are made using established procedures in the art and can be screened using standard assays known in the art, some of which are described below and in the Examples.
Polynucleotides, vectors, and host cells
The invention also provides polynucleotides encoding any of the anti-NGF antibodies as described herein. In one aspect, the invention provides a method of making any of the polynucleotides described herein. Polynucleotides can be made and expressed by procedures known in the art.
In another aspect, the invention provides compositions (such as a pharmaceutical compositions) comprising any of the polynucleotides of the invention. In some embodiments, the composition comprises an expression vector comprising a polynucleotide encoding any of the anti-NGF antibodies described herein.
In another aspect, provided is an isolated cell line that produces the anti-NGF antibodies as described herein.
Polynucleotides complementary to any such sequences are also encompassed by the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNAor synthetic) or RNA molecules. RNA molecules include FlnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.
Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes an antibody or a fragment thereof) or may comprise a variant of such a sequence. Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not diminished, relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide may generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably, at least about 80% identity, yet more preferably, at least about 90% identity, and most preferably, at least about 95% identity to a polynucleotide sequence that encodes a native antibody or a fragment thereof.
Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, or 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
Optimal alignment of sequences for comparison may be conducted using the MegAlign® program in the Lasergene® suite of bioinformatics software (DNASTAR®, Inc., Madison, Wl), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O., 1978, A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M., 1989, CABIOS 5:151-153; Myers, E.W. and Muller W„ 1988, CABIOS 4:11-17; Robinson, E.D., 1971, Comb. Theor. 11 :105; Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R., 1973, Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730.
Preferably, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.
Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementary sequence).
Suitable “moderately stringent conditions” include prewashing in a solution of 5 X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50°C-65°C, 5 X SSC, overnight; followed by washing twice at 65°C for 20 minutes with each of 2X, 0.5X and 0.2X SSC containing 0.1 % SDS.
As used herein, "highly stringent conditions" or "high stringency conditions" are those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at42°C; or (3) employ 50% formamide, 5 x SSC (0.75 M NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt’s solution, sonicated salmon sperm DNA (50 pg/ml), 0.1% SDS, and 10% dextran sulfate at 42°C, with washes at 42°C in 0.2 x SSC (sodium chloride/sodium citrate) and 50% formamide at 55°C, followed by a high-stringency wash consisting of 0.1 x SSC containing EDTA at 55°C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.
It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).
The polynucleotides of this invention can be obtained using chemical synthesis, recombinant methods, or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of skill in the art can use the sequences provided herein and a commercial DN A synthesizer to produce a desired DNA sequence.
For preparing polynucleotides using recombinant methods, a polynucleotide comprising a desired sequence can be inserted into a suitable vector, and the vector in turn can be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides may be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The polynucleotide so amplified can be isolated from the host cell by methods well known within the art. See, e.g., Sambrook et al., 1989.
Alternatively, PCR allows reproduction of DNA sequences. PCR technology is well known in the art and is described in U.S. Patent Nos. 4,683,195, 4,800,159, 4,754,065 and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994. RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those of skill in the art, as set forth in Sambrook et al., 1989, supra, for example.
Suitable cloning vectors may be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones containing the vector. Suitable examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBSSK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial vendors such as BioRad, Strategene, and Invitrogen.
Expression vectors are further provided. Expression vectors generally are replicable polynucleotide constructs that contain a polynucleotide according to the invention. It is implied that an expression vector must be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno- associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO 87/04462. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional controlling elements (such as promoters, enhancers and terminator). For expression (i.e., translation), one or more translational controlling elements are also usually required, such as ribosome binding sites, translation initiation sites, and stop codons.
The vectors containing the polynucleotides of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation, transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipofection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of introducing vectors or polynucleotides will often depend on features of the host cell.
The invention also provides host cells comprising any of the polynucleotides described herein. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include but not limited to COS, HeLa, and CHO cells. See also PCT Publication No. WO 87/04462. Suitable non mammalian host cells include prokaryotes (such as E. coli or B. subtiHis) and yeast (such as S. cerevisae, S. pombe or K. lactis ). Preferably, the host cells express the cDNAs at a level of about 5 fold higher, more preferably, 10 fold higher, even more preferably, 20 fold higher than that of the corresponding endogenous antibody or protein of interest, if present, in the host cells. Screening the host cells for a specific binding to NGFis effected by an immunoassay or FACS. A cell overexpressing the antibody or protein of interest can be identified.
Figure imgf000044_0001
The invention also provides pharmaceutical compositions comprising an effective amount of tanezumab as described herein, and such pharmaceutical compositions for use in methods of treatment as described herein. Examples of such compositions, as well as how to formulate, are also described herein.
It is understood that the compositions can comprise more than one anti-NGF antibody.
The composition used in the present invention can further comprise pharmaceutically acceptable carriers, excipients, or stabilizers (Remington: The Science and practice of Pharmacy 20th Ed., 2000, Lippincott Williams and Wilkins, Ed. K. E. Floover), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Pharmaceutically acceptable excipients are further described herein.
Tanezumab, and compositions thereof, can also be used in conjunction with, or administered separately, simultaneously, or sequentially with other agents that serve to enhance and/or complement the effectiveness of the agents.
Methods for treating cancer pain
In one aspect, the invention provides a method for treating cancer pain in a patient as defined herein.
In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy.
In some embodiments, the method described herein does not comprise administration of an NSAID to the patient. In some embodiments, the method described herein does not comprise administration of an opioid to the patient.
With respect to all methods described herein, reference to anti-NGF antibodies also includes compositions comprising one or more additional agents. These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients including buffers, which are well known in the art. The present invention can be used alone or in combination with other methods of treatment.
Various formulations of an anti-NGF antibody may be used for administration. Pharmaceutically acceptable excipients are known in the art, and are relatively inert substances that facilitate administration of a pharmacologically effective substance. For example, an excipient can give form or consistency, or act as a diluent. Suitable excipients include but are not limited to stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, buffers, and skin penetration enhancers. Excipients as well as formulations for parenteral and nonparenteral drug delivery are set forth in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000.
In some embodiments, these agents are formulated for administration by injection (e.g., intraperitoneally, intravenously, subcutaneously, intramuscularly, intraarticularly, epidurally, intrathecally, injection into the intervertebral disc, etc.). Accordingly, these agents can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history.
In some embodiments tanezumab is administered in a formulation described in WO201 0/032220, herein incorporated by reference.
In some embodiments, the formulation is a liquid formulation and comprises an anti-NGF antibody at a concentration of about 20 mg/ml; and a histidine buffer.
In some embodiments, the formulation further comprises a surfactant which may be polysorbate 20. In some embodiments, the formulation further comprises trehalose dehydrate or sucrose. In some embodiments, the formulation further comprises a chelating agent, which may be EDTA; in some embodiments disodium EDTA. In some embodiments, the formulation is of pH 6.0 ± 0.3.
In some embodiments, the formulation comprises about 20 mg/ml tanezumab; about 10 mM histidine buffer; about 84 mg/ml trehalose dehydrate; about 0.1 mg/ml Polysorbate 20; about 0.05 mg/mldisodium EDTA; wherein the formulation is of a pH 6.0 ± 0.3.
In some embodiments, the formulation has a total volume of about 1 ml.
In some embodiments the formulation is contained in a glass or plastic vial or syringe. In some embodiments the formulation is contained in a pre-filled glass or plastic vial or syringe.
Tanezumab can be administered every eight weeks. For repeated administrations over several doses, the treatment is sustained until a desired suppression of signs and symptoms of cancer pain occurs. The progress of this therapy can be monitored by conventional techniques and assays.
The dosing regimen can vary over time. For example, in some embodiments, the dosage is 20 mg administered every eight weeks. In some embodiments the dosage can be decreased or increased subsequent administrations. For example, the dosage of 20 mg can be administered at start of therapy and then a dosage of 10 mg can be administered at eight weeks, with a dosage of 10 mg being administered at sixteen weeks and each subsequent eight weekly dosage. In addition, as another example, the dosage of 20 mg can be administered at start of therapy and at eight weeks, with a dosage of 10 mg being administered at sixteen weeks and each subsequent eight weekly dosage. In addition, as another example, the 20 mg dosage can be administered at start of therapy and then for one, two, or more eight weekly dosages before subsequent dosages of 10 mg every eight weeks are administered.
In some embodiments a loading dose (or induction dose) is administered followed by the administration of maintenance doses at a lower amount or at lower frequency.
Administration of tanezumab as described herein in accordance with the method in the present invention can be continuous or intermittent, depending, for example, upon the recipient’s physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of tanezumab may be essentially continuous over a preselected period of time or may be in a series of spaced doses.
In some embodiments, more than one anti-NGF antibody may be present. At least one, at least two, at least three, at least four, at least five different, or more anti-NGF antibodies can be present. Generally, those anti-NGF antibodies may have complementary activities that do not adversely affect each other.
In some embodiments, tanezumab may be administered in combination with the administration of one or more additional therapeutic agents.
In some embodiments, tanezumab administration is combined with a treatment regimen further comprising a traditional therapy including surgery.
Formulations
Therapeutic formulations of the anti-NGF antibody used in accordance with the present invention are prepared for storage by mixing the protein having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).
Liposomes containing the anti-NGF antibody are prepared by methods known in the art, such as described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000).
Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid. The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Therapeutic anti-NGF antibody compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
The compositions according to the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, ora non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.
The emulsion compositions can be those prepared by mixing an anti-NGF antibody with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
In embodiments that refer to a method of treating cancer pain as described herein, such embodiments are also further embodiments of tanezumab for use in that treatment, or alternatively of the use of tanezumab in the manufacture of a medicament for use in that treatment.
Kits The invention also provides kits comprising tanezumab described herein. Kits of the invention include one or more containers comprising tanezumab and instructions for use in accordance with any of the methods of the invention described herein. Generally, these instructions comprise a description of administration of the anti-NGF antibody for the above described therapeutic treatments. In some embodiments, kits are provided for producing a single-dose administration unit. In certain embodiments, the kit can contain both a first container having a dried protein and a second container having an aqueous formulation. In certain embodiments, kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.
The instructions relating to the use of the anti-NGF antibody generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
The kits of this invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump. A kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-NGF antibody. The container may further comprise a second pharmaceutically active agent.
Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.
Example 1: The study was a randomized, double-blind, placebo-controlled, multicenter, parallel- group, 48-week Phase 3 study in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy. Eligible subjects had cancer diagnosed as having metastasized to bone or had multiple myeloma with imaging confirmation of bone metastasis at Screening or within 120 days prior to the Screening visit according to local standard of care (e.g., via bone scan, magnetic resonance imaging (MRI), computed tomography (CT) scan, or positron emission tomography- computed tomography (PET-CT) scan). Subjects were required to have an average pain score >5 at Screening and Baseline for the index bone metastasis cancer pain site, a Patient’s Global Assessment of Cancer Pain assessed as ‘fair’, ‘poor’ or ‘very poor’ at Screening and at Baseline, and an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1 , or 2 at Screening. Subjects were expected to require daily opioid medication throughout the course of the study.
Approximately 144 subjects (72/treatment arm) were planned to be randomized to receive tanezumab 20 mg or matching placebo in 3 SC injections at Baseline, Week 8 and Week 16, in addition to background opioids administered throughout the study.
The protocol was initially designed to include 3 treatment groups (tanezumab 20 mg SC, tanezumab 10 mg SC, and placebo) with a 1 :1 :1 randomization ratio, but was amended (Amendment 3) after study start to discontinue the tanezumab 10 mg dose arm. Altogether, 10 subjects in total were randomized to receive tanezumab 10 mg SC prior to implementation of Amendment 3. Subjects who were randomized to tanezumab 10 mg SC at baseline and later received tanezumab 20 mg SC after Amendment 3 are labeled as tanezumab 10/20 mg group.
Thus, the treatment groups were:
• Placebo and tanezumab 20 mg in a 1 :1 ratio
• 9 subjects randomized to tanezumab 10 mg
• 1 subject randomized to tanezumab 10 mg and later changed to 20 mg after the implementation of Amendment 3 Based on the study objectives, the 9 subjects in the tanezumab 10 mg and 1 subject in the tanezumab 10/20 mg treatment group are only used to provide supplemental safety information.
The opioid regimen for each subject was optimized prior to Baseline. Subjects on a stable opioid regimen who met the criteria for randomization during the Baseline Assessment Period continued on the same opioid regimen with only minimal dosage increases (< 10% of baseline total daily dose) permitted for the first 8 weeks of the Double-Blind Treatment Period.
Stratification variables were (i) tumor aggressiveness (assessed by ECOG performance status) and (ii) presence/absence of concomitant anticancer treatment (e.g., chemotherapy or hormonal therapy or anti hormonal therapy).
The primary efficacy endpoint was measured 8 weeks after the 1st dose at Baseline. The end of the double-blind treatment period was at Week 24, followed by a 24-week safety follow-up period, resulting in the end of study at Week 48. The study had a Group Sequential Design with a single interim analysis performed after at least 50% of subjects had completed or discontinued prior to Week 8. The interim analysis assessed both futility (non-binding) and efficacy based on the primary efficacy parameter. The study did not stop based on the interim analysis. As a result, the alpha used for final analysis was not 0.05, but was determined based on the number of subjects included in the interim analysis and in the final analysis using the Lan DeMets alpha spending function with the O’Brien Fleming style boundary, which was implemented in EAST version 6.5. The alpha-level used for a two-sided test of the primary endpoint in the final analysis was 0.0478.
The study design is illustrated in Figure 1.
Subject Population
The primary analysis set for efficacy is the modified intent to treat (mITT) analysis set. It is labeled as the “mITT Population” and consists of all subjects who were randomized to either tanezumab 20 mg or placebo SC and received at least one dose of SC study medication. The safety analysis set is defined as all subjects treated with tanezumab or placebo SC and is labeled as the ‘Safety Analysis Set’ or ‘Safety Population’. This set also includes 10 subjects who were randomized and received tanezumab 10 mg: 9 remained on tanezumab 10 mg SC and 1 changed to tanezumab 20 mg SC after the implementation of Amendment 3.
• Subject disposition
• Screened: 325
• Randomized: 156 o Randomized to placebo or tanezumab 20 mg: n=146 o Randomized to tanezumab 10 mg prior to Amendment 3: n=10
Table 2: Summary of Subject Evaluation and Disposition Events for Placebo and Tanezumab 20 mg (Primary Analysis Set)
Figure imgf000054_0001
Figure imgf000055_0001
Table 3: Selected Demographic and Baseline Characteristics
Figure imgf000055_0002
Figure imgf000056_0001
Efficacy: Key Results & Supportive Findings
Primary Endpoint: Change from Baseline to Week 8 in Average Pain Intensity at the Index Cancer Pain Site.
Treatment with tanezumab 20 mg SC resulted in significant improvement (reduction) in the daily average pain intensity score compared to placebo treatment and met the primary objective of the study.
Change (mean ± SD) from Baseline to Week 8 on the 11 -point numerical pain score (ranging from 0=no pain to 10=worst pain) was -1.92 ± 2.27 in the tanezumab 20 mg group and -1.15 ± 1.16 in the placebo group. After multiple imputation accounting for missing data, the Least Square mean change (LS mean (95% Cl)) was -2.03 (-2.73, - 1.33) in the tanezumab 20 mg, compared to -1.25 (-1.94, -0.55) in the placebo group, reflecting a statistically significant (p = 0.0381 with a = 0.0478) improvement over placebo, LS mean difference (95% Cl) = -0.78 (-1.52, -0.04). See Figure 2.
A consistent benefit of treatment with tanezumab 20 mg versus placebo was observed regardless of region, baseline pain score, primary cancer type, baseline opioid use, tumor aggressiveness, or concomitant anticancer treatment.
Statistical significance:
Because an interim analysis was performed when 86 subjects had completed the primary assessment at Week 8, the type-l error (alpha-level) for the final analysis was determined based on the pre-specified Lan-DeMets alpha-spending function with the O’Brien Fleming style boundary. The alpha-level used for a two-sided test of the primary endpoint in the final analysis of the 145 subjects was 0.0478.
Effect of Amendment 3: Similar results were observed when the analysis of the primary endpoint was repeated among subjects randomized after Protocol Amendment 3. The improvement in LS mean (95% Cl) was -2.14 (-2.89, -1.40) in the tanezumab 20 mg compared to -1.15 (- 1.86, -0.44) in the placebo group, showing an LS mean difference (95% Cl) of -1.00 (- 1.77, -0.22).
Secondary Endpoints Based on Pain Scores
Improvements in average pain were also greater with tanezumab 20 mg than with placebo at Weeks 1, 2, 4, and 6 (Figure 3A). Changes in average pain were not different between the two groups beyond Week 8. Improvements in worst pain intensity at the index cancer pain site were also observed with tanezumab 20 mg compared with placebo at Weeks 2, 4, and 6; significant differences between the two groups were not evident at or beyond Week 8 (Figure 3B). Figure 4 provides the improvement in the average pain intensity up to Day 7.
Results of the primary analysis were supported by the higher proportion of subjects in the tanezumab 20 mg group who achieved >= 30%, 50%, 70% or 90% reduction from baseline in pain score. At Week 8, 18 (25.4%) subjects in the tanezumab 20 mg group achieved >=50% reduction, significantly more than the 9 (12.3%) subjects in the placebo group (Odds Ratio=2.55, p=0.0405). See Figure 5 in this regard and also Figure 6 showing the >=50% response rates over time . The worst pain intensity score at the index cancer pain site also showed greater average improvement (LS mean, 95% Cl) in the tanezumab 20 mg group than in the placebo group, statistically significant at Weeks 2, 4 and 6 (Figure 3B). At Week 8, the improvement was numerically larger in the tanezumab 20 mg group (-2.14, [-2.88, -1.41]) than in the placebo group (-1.38, [- 2.10, - 0.67]). Flowever, the LS mean difference (-0.76) was not statistically significant p=0.0505. Nevertheless, a higher proportion of subjects in the tanezumab 20 mg group achieved >=50% reduction in worst pain intensity score at Weeks 4 and 6, as well as at Week 8: 16 (22.5%) vs 7 (9.6%), Odds Ratio=2.69, p=0.0457.
Other Secondary Endpoints Patient Global Assessment of Cancer Pain
Starting from Week 4 throughout the study, numerically greater improvement (reduction) in Patient Global Assessment of Cancer Pain was observed in the tanezumab 20 mg group than in the placebo group. However, the difference did not reach statistical significance when the improvement was compared between treatment groups at each individual visit other than Week 4.
At Week 8, the improvement (reduction in mean (95% Cl)) in Patient Global Assessment of Cancer Pain on a 5-point scale (from 1=very good to 5=very poor) was - 0.74 (-3, -1) in the tanezumab 20 mg and -0.54 (-3, 1) in the placebo group. After multiple imputation accounting for missing data, the Least Square mean (LS mean,
95% Cl) was -0.56 (-0.89, -0.23) in the tanezumab 20 mg group, compared to -0.23 (- 0.55, 0.09) in the placebo group, an LS mean difference (95% Cl) of - 0.33 (-0.67,
0.02), although the difference was not statistically significant (p=0.0637). Numerically more subjects in the tanezumab 20 mg group achieved a 2-point reduction on the 5- point scale than in the placebo group, 12 (16.7%) vs 10 (13.7%).
• Average Daily Dosage of Opioids and Frequency of Opioids Use
At baseline, the mean (median) daily dosage of opioids was 183 (90) Milligram Morphine Equivalent (MME) in the placebo group, and 190 (85) MME in the tanezumab 20 mg group. The average daily dosage remained between 170 and 190 MME for both groups through Week 16. At Week 24, the mean (SD) daily dosage of opioids was 190 (353) MME in the placebo group, and 347 (1537) MME in the tanezumab 20 mg group. The higher dose in the tanezumab group was due to an extreme value of 12746 MME. The median daily dose at Week 24 was 61 MME in both treatment groups.
At Baseline, the rescue medication was used on average 0.92 times per day in the tanezumab 20 mg group and 1.26 times/day in the placebo group. After baseline, rescue medication continued to be used less frequently in the tanezumab 20 mg group than in the placebo group, ranging from 25% (95% Cl: 4%- 42%) less at Week 4 to 10% less at Week 24. Subgroup Analysis
Interaction analysis for the primary endpoint were conducted to explore how the following factors affected the treatment effect:
- Region (Asia, Europe and Latin America)
- Baseline pain score (<median pain score or >median pain score)
- Primary cancer type (breast carcinoma, lung carcinoma, prostatic carcinoma, and other carcinomas o Other carcinomas (pooled subjects for carcinomas with fewer that 10 subjects in both the tanezumab 20 mg and placebo treatment groups) including bone marrow, bone metastasis, cervical cancer, cholangiocarcinoma, colorectal carcinoma, corpus uteri carcinoma, gastric carcinoma, head of pancreas carcinoma, larynx epidermoid carcinoma, myeloma, nasopharynx carcinoma, pancreatic neuroendocrine tumors, rectal carcinoma, renal carcinoma, sublingual gland cancer, and uterine carcinoma
- Baseline opioid use ((<median opioid use or >median opioid use)
- Tumor aggressiveness as measured by ECOG Performance Status Score at screening/baseline (less aggressive (<1) or more aggressive (>2))
- Concomitant anticancer treatment (present or absent)
The consistent benefit of treatment with tanezumab 20 mg versus placebo was observed regardless of region, baseline pain score, primary cancer type, baseline opioid use, tumor aggressiveness, or concomitant anticancer treatment (except for other carinomas at Week 1 [LS mean difference: 0.14])
The results of these analyses can be seen in Figures 9-14:
- index cancer pain site (Figure 9)
- geographic region (Figure 10)
- median pain score at baseline (Figure 11)
- median opioid use at baseline (Figure 12). The median opioid use is the median value of baseline opioid use, equal to 96 mg of morphine equivalence. - tumor aggressiveness (Figure 13). Aggressiveness of tumor was evaluated by ECOG Performance Status Score: ECOG Performance Status Score at Screening of <1 is evaluated as less aggressive and >2 is evaluated as more aggressive.
- concomitant anti-cancer therapy (Figure 14).
The analyses revealed subgroups with statistically significant differences at Week 8. These subgroups included:
- “Other” primary tumor types (Figure 9)
- patients with baseline pain score above median (6.0) (Figure 11)
- patients with opioid use < median at baseline (96 MME) (Figure 12)
- less aggressive tumors (Figure 13)
- no concomitant anticancer therapy (Figure 14)
At week 8, a larger treatment difference was observed for subjects with a baseline pain score above the median pain score (LS mean difference (SE): -1.49 (0.61); p=0.0178) than for subjects with baseline pain score below or equal to the median pain score (LS mean difference (SE): -0.53 (0.47); p=0.2621).
At week 8, a larger treatment difference was observed for subjects with a baseline opioid use below or equal to the median opioid use (LS mean difference (SE): -1.25 (0.50); p=0.0151 ) than for subjects with baseline opioid use above the median opioid use (LS mean difference (SE): -0.69 (0.53); p=0.2034).
Safety
The safety population consisted of 73 subjects in the placebo SC group, 72 subjects in the tanezumab 20 mg SC group, 9 subjects who received tanezumab 10 mg SC, and 1 subject in the tanezumab 10/20 mg SC group. The proportion of subjects that received three planned SC doses of study medication were 52.1%, 65.3%, and 66.7% in the placebo, tanezumab 20 mg, and tanezumab 10 mg treatment groups, respectively. Treatment-emergent adverse events are shown in Table 4. The incidence of adverse events was 68.5% in the placebo group, 73.6% in the tanezumab 20 mg group, 88.9% (8 of 9) in the tanezumab 10 mg group and 100% (1 of 1) in the tanezumab 10/20 mg group. The incidence of serious adverse events was 30.1% (placebo group), 40.3% (tanezumab 20 mg group), 22.2% (2 of 9, tanezumab 10 mg group) and 100% (1 of 1, tanezumab 10/20 mg group). The total number of deaths reported in the study was 46 and none was considered treatment-related by the investigators. The incidence of discontinuations from the study due to AEs was 9.6% in the placebo group and 6.9% in the tanezumab 20 mg group whereas the incidence of discontinuations from the study drug (but not the study) due to AEs was 6.8% in the placebo group and 5.6% in the tanezumab 20 mg group.
Table 4 Incidence of Treatment-Emergent Adverse Events During the Treatment Period (All Causalities) - Safety Population
Figure imgf000061_0001
The most frequent adverse events (>2% of subjects all causalities for the placebo and tanezumab 20 mg treatment groups) are shown in Table 5. Anaemia was the most commonly reported AE with an incidence of 12.3% and 8.3% in the placebo and tanezumab 20 mg SC treatment groups, respectively. The second most commonly reported AEs were arthralgia and progression of prostate cancer both with an incidence of 8.2% and 8.3% in the placebo and tanezumab 20 mg SC treatment groups, respectively. Peripheral neurologic adverse events of abnormal peripheral sensation reported in > 2% of subjects were limited to paraesthesia (0% placebo; 2.8% tanezumab 20 mg) and neuralgia (2.7% placebo; 1.4% tanezumab 20 mg). Table 5 Incidence of Most Frequent (>2%) Treatment-Emergent Adverse Events During the Treatment Period (All Causalities) - Safety Population
Figure imgf000062_0001
Figure imgf000063_0001
A summary of joint safety events that required adjudication is shown in Table 6. Overall, 1 subject each in the placebo SC and tanezumab 10 mg SC treatment groups, and 2 subjects in the tanezumab 20 mg SC treatment group had joint safety events that required adjudication; none were considered related to study treatment by the investigators. The joint safety events were adjudicated to the following outcomes:
Other — traumatic avulsion fracture of the ankle (placebo), Other — extra-articular pathologic fracture (tanezumab 10 mg), and pathologic fractures - left acetabulum and right hip respectively (2 subjects-tanezumab 20 mg). One subject in the tanezumab 20 mg group with a reported pathologic fracture of the left acetabulum on Study Day 31 had a total joint replacement (TJR) of the left hip 2 days after the subject discontinued the study due to a non-serious adverse event of pathologic fracture of left acetabulum. Both pathological fractures occurred at a site of pre-existing bone metastasis and the subject with the fracture of the left acetabulum had received prior radiotherapy of the left hemipelvis. The subject who had TJR of the left hip had no evidence of OAat Screening (Baseline KL grade 0). No subject in any treatment group had a joint safety event adjudicated as rapidly progressive OA, primary osteonecrosis, or subchondral insufficiency fracture. Table 6 Summary of Subjects with Adjudicated Joint Safety Outcomes - Safety Population
Figure imgf000064_0001
Interpretation of Primary Results
The primary endpoint of the study was met. Statistically significant changes from Baseline to Week 8 in the daily average pain intensity in the index bone metastasis cancer pain site were achieved for tanezumab 20 mg SC treatment compared to placebo SC treatment, each administered in addition to background opioids. The use of background opioids allowed an appropriate comparison of the efficacy and safety of tanezumab versus placebo to be made reflective of the real-world experience. A number of secondary efficacy endpoints supported the primary endpoint of the study. Tanezumab 20 mg demonstrated significantly greater improvements vs placebo in the daily average pain intensity and in the daily worst pain intensity in the index bone metastasis cancer pain site at Weeks 2, 4 and 6. Tanezumab 20 mg also demonstrated a significantly greater proportion of subjects with a 50% response at Week 8 compared to placebo.
The safety findings including the adverse event profile in the tanezumab treatment groups were generally consistent with those anticipated in subjects with cancer pain predominantly due to bone metastasis and/or the known safety profile of tanezumab.
No new safety risks were identified.

Claims

Claims
1. A method of treating cancer pain in a patient in need thereof, the method comprising administering 20 mg of tanezumab subcutaneously to the patient, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis, cancer originated in bone, or multiple myeloma, and wherein the patient has had inadequate pain relief with opioid analgesics.
2. The method according to claim 1 , wherein the patient has: i. an average Pain Score of at least 5 for the index cancer pain site; ii. a Patient's Global Assessment of Cancer Pain of "fair", "poor" or "very poor"; iii. an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1, or 2; and iv. no joint safety event selected from: 1) rapidly progressive osteoarthritis (type 1 or type 2), 2) atrophic or hypotrophic osteoarthritis, 3) subchondral insufficiency fracture, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
3. The method according to claim 1 or 2, wherein tanezumab is administered every eight weeks.
4. The method according to any one of the preceding claims, wherein tanezumab is administered for at least two or more doses at eight weekly intervals.
5. The method according to any one of the preceding claims, wherein the tanezumab is administered to the patient for at least 8, 16, 24, 32, 40 or 48 weeks.
6. The method according to any one of the preceding claims, wherein the treatment effectively reduces pain at the index cancer pain site.
7. The method according to any one of the preceding claims, wherein the treatment effectively reduces average pain intensity at the index cancer pain site.
8. The method according to any one of the preceding claims, wherein the treatment effectively reduces worst pain intensity at the index cancer pain site.
9. The method accordingly to any one of the preceding claims, wherein the treatment effectively reduces patient global assessment of cancer pain at the index cancer pain site.
10. The method according to any one of any one of the preceding claims, wherein the treatment effectively reduces pain at the index cancer pain site at at least 1 , 2, 3, 4, 5, 6, 7, or 8 week(s) after start of treatment.
11. The method according to claim any one of the preceding claims, wherein the treatment effectively reduces pain at the index cancer pain site at weeks 2, 4, and 6, in addition to week 8 after start of treatment.
12. The method according to any one of any one of the preceding claims, wherein the treatment effectively reduces pain at the index cancer pain site at at least 16, 24, 32, 40, 48 or 56 weeks after start of treatment.
13. The method according to any one of the preceding claims, wherein the treatment effectively improves pain at the index cancer pain site compared to a baseline value prior to or at start of treatment.
14. The method according to any one of the preceding claims, wherein the patient requires background opioid therapy.
15. The method according to any one of the preceding claims, wherein the patient requires opioid medication.
16. The method according to any one of the preceding claims, wherein treatment results in reduced opioid use.
17. The method according to any one of the preceding claims, wherein the treatment results in reduced average opioid consumption.
18. The method according to any one of the preceding claims, wherein the patient is subjected to radiographic assessment of the knee, hip and/or shoulder prior to starting treatment.
19. The method according to claim 18, wherein if radiographic assessment identified rapidly progressive osteoarthritis of the joint, the patient is excluded from the treatment with tanezumab.
20. The method of any one of the preceding claims, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis.
21. The method according to any one of the preceding claims, wherein the patient has an average pain score of greater than 5 at the index cancer pain site.
22. The method according to claim 21, wherein the patient has an average pain score of about 6 at the index cancer pain site.
23. The method according to any one of the preceding claims, wherein the patient has a total weekly opioid use of less than 150, 125, 100, or 75 morphine equivalents.
24. The method according to claim 23, wherein the patient has a total weekly median opioid use of less than about 100 morphine equivalents.
25. The method according to any one of the preceding claims, wherein the cancer is diagnosed as having metastasized to bone or multiple myeloma.
26. The method according to any one of the preceding claims, wherein the cancer pain is from cancer originated in bone.
27. The method according to claim 26, wherein the cancer pain is from osteosarcoma.
28. The method according to any one of claims 1 to 24, wherein the cancer pain is from cancer metastasized to bone.
29. The method according to claim 28, wherein the cancer pain is from prostate cancer metastasized to bone, breast cancer metastasized to bone, lung cancer metastasized to bone, sarcoma metastasized to bone, or renal cancer metastasized to bone.
30. The method according to claim 28, wherein the cancer pain is from cancer other than breast cancer, prostate cancer or lung cancer metastasized to bone.
31. The method of any one of the preceding claims, wherein the patient has had cancer pain predominantly due to bone metastasis for at least three months.
32. The method of any one of the preceding claims, wherein the tumor is less aggressive as measured by ECOG Performance Status Score.
33. The method of claim 32, wherein the ECOG Performance Status Score is less than or equal to 1.
34. The method of any one of the preceding claims, wherein the patient does not receive concomitant anti-cancer therapy.
35. The method according to any one of the preceding claims, wherein the patient prior to administering tanezumab has no symptoms and radiographic evidence of osteoarthritis of the knee, hip or shoulder and/or of osteonecrosis or osteoporotic fracture.
36. The method according to any one of the preceding claims, wherein the method further comprises conducting a radiographic assessment of the knee, hip and/or, shoulder at regular intervals.
37. Tanezumab for use in a method of treating cancer pain in a patient in need thereof, the method comprising administering 20 mg of tanezumab subcutaneously to the patient, wherein the patient has moderate to severe cancer pain predominantly due to bone metastasis, cancer originated in bone, or multiple myeloma, and wherein the patient has had inadequate pain relief with opioids.
38. Tanezumab for use of claim 37, wherein the method is as defined in any one of claims 1 to 36.
PCT/IB2022/056903 2021-07-27 2022-07-26 Method of treatment of cancer pain with tanezumab WO2023007374A1 (en)

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