Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
  • A61K2039/507—Comprising a combination of two or more separate antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

• the present invention relates to uses and compositions comprising an anti-CTLA4 antibody and at least one therapeutic agent for treatment of cancer.
• the invention further relates to administering, in addition to the antibody-therapeutic agent inhibitor combination, at least one additional therapy such as, among others, additional therapeutic agents, radiation and stem cell transplant.
• cancer antitumor agents act by a variety of mechanisms that inhibit cancer cell growth and division, ultimately destroying the malignant cell. However, because these cytotoxic agents are generally not selective for neoplastic cells, they destroy normal cells, disrupt physiologic functions, and are often associated with adverse effects.
• An alternative approach to cancer therapy is to target the immune system (“immunotherapy") rather than the tumor itself so that the patient's own immune system attacks tumors while sparing non-tumor cells.
• One cancer immunotherapy approach targets cytotoxic T lymphocyte-associated antigen 4 (CTLA4; CD152), which is a cell surface receptor expressed on activated T cells.
• CTL4 cytotoxic T lymphocyte-associated antigen 4
• CTLA4 Binding of CTLA4 to its natural ligands, B7.1 (CD80) and B7.2 (CD86), delivers a negative regulatory signal to T cells, and blocking this negative signal results in enhanced T cell immune function and antitumor activity in animal models (Thompson and Allison Immunity 7:445-450 (1997); McCoy and LeGros lmmunol.& Cell Biol. 77:1-10 (1999)).
• CTLA4 blockade using antibodies markedly enhances T cell- mediated killing of tumors and can induce antitumor immunity (see, e.g., Leach et al., Science 271:1734-1736 (1996); Kwon et al. Proc. Natl. Acad.
• CTLA4 antibodies and their uses are described in, e.g., the following applications and patents: U.S. Patent Application No. 09/472,087, now issued as U.S. Patent No. 6,682,736; Int. Appl. No. PCT/US99/30895 (published June 29, 2000, as WO 00/37504); U.S. Pat. Appl. No.
• the present invention includes a method for the treatment of cancer in a patient in need of such treatment.
• the method comprises administering to the patient a therapeutically effective amount of an anti-CTLA4 antibody, e.g., ipilimumab (also referred to as MDX-010) and CP-675,206 (also referred to as 11.2.1. and ticilimumab), in combination with a therapeutically effective amount of at least one therapeutic agent, wherein the cancer and the agent are selected from the group consisting of:
• the cancer is non-Hodgkin's lymphoma (NHL) and wherein the agent is rituximab;
• the cancer is NHL and the agent is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP);
• the cancer is NHL and the agent is cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOP-R);
• the cancer is lung cancer and the agent is bevacizumab;
• the cancer is non-small cell lung cancer (NSCLC) and the agent is gefitinib;
• the cancer is NSCLC and the agent is bevacizumab;
• the cancer is NSCLC and the agent is a taxane and gemcitabine, and further wherein the taxane is selected from the group consisting of docetaxel and paclitaxel;
• the cancer is NSCLC and the agent is a taxane and a platinum compound;
• the cancer is NSCLC and the agent is docetaxel; 0) the cancer is NSCLC and the agent is erlotinib;
• the cancer is NSCLC and the agent is pemetrexed;
• the cancer is NSCLC and the agent is a platinum compound;
• the cancer is gastric cancer and the agent is irinotecan;
• the cancer is gastric cancer and the agent is fluorouracil and leucovorin;
• the cancer is liver cancer and the agent is doxorubicin, ifosfamide and vincristine;
• the cancer is liver cancer and the agent is doxorubicin and vincristine;
• the cancer is colorectal carcinoma (CRC) and the agent is fluorouracil;
• the cancer is CRC and the agent is capecitabine;
• the cancer is CRC and the agent is fluorouracil, leucovorin, and oxaliplatin (FOLFOX);
• the cancer is CRC and the agent is fluorouracil, leucovorin, and irinotecan (FOLFIRI);
• the cancer is CRC and the agent is cetuximab;
• the cancer is chronic myeloid leukemia (CML) and the agent is imatinib mesylate;
• the cancer is chronic lymphocytic leukemia (CLL) and the agent is imatinib mesylate;
• the cancer is pancreatic cancer and the agent is gemcitabine;
• the cancer is breast cancer and the agent is a taxane;
• the cancer is breast cancer and the agent is cyclophosphamide, doxorubicin and a taxane;
• the cancer is breast cancer and the agent is selected from the group consisting of tamoxifen, anastrazole, letrozole, and fulvestrant;
• the cancer is breast cancer and the agent is trastuzumab;
• cancer is breast cancer and the agent is bevacizumab;
• the cancer is breast cancer and the agent is cetuximab;
• the cancer is breast cancer and the agent is axitinib;
• the cancer is bladder cancer and the agent is Bacillus Calmette-Guerin (BCG);
• BCG Bacillus Calmette-Guerin
• gg the cancer is bladder cancer and the agent is gemcitabine and cisplatin;
• the cancer is multiple myeloma and the agent is bortezomib;
• the cancer is multiple myeloma and the agent is dexamethasone and thalidomide; and (kk) the cancer is ovarian cancer and the agent is carboplatin and paclitaxel.
• the treatment is selected from the group consisting of neoadjuvant therapy, adjuvant therapy, first-line therapy, second-line therapy, and third-line therapy.
• the agent is administered sequentially or contemporaneously with the antibody.
• the taxane is paclitaxel and the platinum compound is carboplatin.
• the method further comprises administering at least one agent selected from the group consisting of bevacizumab, PF03512676, and sunitinib. In another aspect, the method further comprises administering at least one agent selected from the group consisting of erlotinib and pemetrexed, wherein the treatment comprises second line therapy.
• the therapeutically effective amount of the antibody ranges from about 1 mg/kg to 40 mg/kg. In another aspect, the therapeutically effective amount of the antibody ranges from about 3 mg/kg to 15 mg/kg.
• the NHL is indolent NHL and the treatment comprises first line therapy.
• the NHL is aggressive NHL and the treatment comprises second line therapy. In a further aspect, the treatment comprises first line therapy.
• the cancer is CRC and the agent is capecitabine and the treatment comprises first line therapy.
• the cancer is CRC and the agent is FOLFOX and the treatment is selected from the group consisting of first line therapy and adjuvant therapy following surgical resection of a primary colon tumor.
• the cancer is CML and the agent is imatinib mesylate and the treatment comprises first line therapy.
• the cancer is CLL and the agent is imatinib mesylate and the treatment comprises first line therapy.
• the cancer is pancreatic cancer and the agent is gemcitabine and the pancreatic cancer is selected from the group consisting of non-resectable Stage II, locally advanced Stage III, and metastatic Stage IV and wherein the treatment comprises first line therapy.
• the cancer is breast cancer and the agent is a taxane and the treatment comprises first line therapy.
• the cancer is ovarian cancer and the agent is carboplatin and paclitaxel and the treatment comprises first line therapy.
• the invention includes a kit for the treatment of NSCLC comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of a carboplatin; a therapeutically effective amount of paclitaxel; an applicator; and an instructional material for the use of the kit.
• the kit further comprises a therapeutically effective amount of at least one agent selected from the group consisting of bevacizumab, sunitinib, and PF03512676.
• the invention includes a kit for the treatment of NSCLC comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of an agent selected from the group consisting of docetaxel, erlotinib and pemetrexed; an applicator; and an instructional material for the use of the kit.
• the invention includes a kit for the treatment of CRC comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of carboplatin; a therapeutically effective amount of paclitaxel; an applicator; and an instructional material for the use of the kit.
• the invention includes a kit for the treatment of CRC comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of a fluorouracil; a therapeutically effective amount of leucovorin; a therapeutically effective amount of oxaliplatin; an applicator; and an instructional material for the use of the kit.
• the invention includes a kit for the treatment of pancreatic cancer comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of gemcitabine; an applicator; and an instructional material for the use of the kit.
• the invention includes a kit for the treatment of ovarian cancer comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of carboplatin; a therapeutically effective amount of paclitaxel; an applicator; and an instructional material for the use of the kit.
• the invention includes a method for preventing or treating infection by HIV or for preventing, treating or delaying the onset of AIDS in a patient in need thereof.
• the method comprises administering to the patient a therapeutically effective amount of anti-CTLA4 antibody CP-675,206 and further comprises administering a therapeutically effective amount of at least one antiviral agent selected from the group consisting of an HIV protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, a nucleoside/nucleotide reverse transcriptase inhibitor, a CCR5 antagonist, an inhibitor of gp120 interaction with CD4, an HIV fusion inhibitor, a HIV integrase inhibitor, an RNaseH inhibitor, a prenylation inhibitor, and a maturation inhibitor.
• the CCR5 antagonist is maraviroc.
• the method further comprises assessing the co-receptor tropism of the HIV.
• the invention includes a method for preventing or treating infection by HIV or for preventing, treating or delaying the onset of AIDS in a patient in need thereof, where the method comprises administering to the patient a therapeutically effective amount of an anti- CTLA4 antibody and maraviroc.
• the anti-CTLA4 antibody is selected from the group consisting of CP- 675,206 and ipilimumab.
• Figure 1 shows the nucleotide and amino acid sequences of anti-CTLA4 antibody 4.1.1.
• Figure 1A shows the full length nucleotide sequence for the 4.1.1 heavy chain (SEQ ID NO:1).
• Figure 1 B shows the full length amino acid sequence for the 4.1.1 heavy chain (SEQ ID NO:2), and the amino acid sequence for the 4.1.1 heavy chain variable region (SEQ ID NO:3) designated between brackets "[ ]".
• the amino acid sequence of each 4.1.1 heavy chain CDR is underlined.
• CDR1 GFTFSSHGMH (SEQ ID NO:4)
• CDR2 VIWYDGRNKYYADSV (SEQ ID NO:5)
• CDR3 GGHFGPFDY (SEQ ID NO:6)
• Figure 1C shows the nucleotide sequence for the 4.1.1 light chain (SEQ ID NO:7)
• Figure 1D shows the amino acid sequence of the full length 4.1.1 light chain (SEQ ID NO:8), and the variable region as indicated between brackets "[ ]" (SEQ ID NO:9).
• CDR1 RASQSISSSFLA (SEQ ID NO:10)
• CDR2 GASSRAT (SEQ ID NO:11)
• CDR3 QQYGTSPWT (SEQ ID NO:12).
• Figure 2 shows the nucleotide and amino acid sequences of anti-CTLA4 antibody 4.13.1.
• Figure 2A shows the full length nucleotide sequence for the 4.13.1 heavy chain (SEQ ID NO: 13).
• Figure 2B shows the full length amino acid sequence for the 4.13.1 heavy chain (SEQ ID NO: 14), and the amino acid sequence for the 4.13.1 heavy chain variable region (SEQ ID NO:15) designated between brackets "[ ]".
• the amino acid sequence of each 4.13.1 heavy chain CDR is underlined.
• CDR1 GFTFSSHGIH (SEQ ID NO:16); CDR2: VIWYDGRNKDYADSV (SEQ ID NO: 12); and CDR3: VAPLGPLDY (SEQ ID NO: 18).
• Figure 2C shows the nucleotide sequence for the 4.13.1 light chain (SEQ ID NO:19).
• Figure 2D shows the amino acid sequence of the full length 4.13.1 light chain (SEQ ID NO:20), and the variable region as indicated between brackets "[ ]" (SEQ ID NO:21 ).
• CDR1 RASQSVSSYLA (SEQ ID NO:22); CDR2: GASSRAT (SEQ ID NO:23); and CDR3: QQYGRSPFT (SEQ ID NO:24).
• Figure 3 shows the nucleotide and amino acid sequences of anti-CTLA4 antibody CP-675,206.
• Figure 3A shows the full length nucleotide sequence for the CP-675,206 heavy chain (SEQ ID NO:25).
• Figure 3B shows the full length amino acid sequence for the CP-675,206 heavy chain (SEQ ID NO:26), and the amino acid sequence for the CP-675,206 heavy chain variable region (SEQ ID NO:27) designated between brackets "[ ]".
• the amino acid sequence of each CP-675,206 heavy chain CDR is underlined.
• CDR1 GFTFSSYGMH (SEQ ID NO:28); CDR2: VIWYDGSNKYYADSV (SEQ ID NO:29); and CDR3: DPRGATLYYYYYGMDV (SEQ ID NO:30).
• Figure 3C shows the nucleotide sequence for the CP-675,206 light chain (SEQ ID NO:31).
• Figure 3D shows the amino acid sequence of the full length CP-675,206 light chain (SEQ ID NO:32), and the variable region as indicated between brackets "[ ]" (SEQ ID NO:33).
• CDR1 RASQSINSYLD (SEQ ID NO:34); CDR2: AASSLQS (SEQ ID NO:35); and CDR3: QQYYSTPFT (SEQ ID NO:36).
• Figure 4 is a graph depicting the plasma serum levels in Rhesus monkeys following exposure to an anti-CTLA4 antibody. All Rhesus monkeys were administered influenza vaccine FLUZONE intramuscularly (IM) on week 0 and again on week 4. In addition to FLUZONE, animals in Group 1 (animal number 1 (closed circle), 2 (closed square), and 3 (closed triangle)) received a single dose of anti-CTL4 antibody 4.1.1 (also referred to as CP- 642,570) at 5 mg/kg intravenously (IV) on week 0. Animals in Group 3 (animal number 4 (open circle), 5 (open square), 6 (open triangle), and 7 (marked by "x”)) received a single dose of an irrelevant human antibody (anti-KLH antibody) at 5 mg/kg IV on week 0.
• FLUZONE intramuscularly
• animals in Group 1 animal number 1 (closed circle), 2 (closed square), and 3 (closed triangle) received a single dose of anti-CTL4 antibody 4.1.1 (also referred to
• Figure 5 is a graph depicting the serum level of a neopterin, a marker which is suggestive of immune activity, in Rhesus monkeys immunized with FLUZONE IM on week 0 and week 4 and administered anti-CTLA4 antibody 4.1.1 at 5 mg/kg IV on week 0.
• Animal number AG40 (closed diamond), number AK80 (closed square) and number AM90 (closed triangle) were in group 1 and received anti-CTLA4 antibody and FLUZONE on day 0 followed by FLUZONE on week 0.
• FIG. 6 is a graph depicting the level of a 2-5 adenylate synthetase in white blood cell pellets isolated from the blood of Rhesus monkeys immunized with FLUZONE IM on weeks 0 and 4 and further administered anti-CTLA4 antibody 4.1.1 (5mg/kg IV) on week 0.
• Peripheral blood cells were obtained from each animal in each group 1 (FLUZONE IM weeks 0 and 4 and anti-CTLA4 antibody week 0) and group 2 (FLUZONE IM on weeks 0 and 4 and an irrelevant antibody (anti-KLH 5 mg/kg IV) administered on week 0) at week 2 (light gray shading), week 4 (darker gray shading) and week 6 (unshaded bars). Where the values exceeded 4000 pmol/dl, the values are shown in each bar. The cells were pelleted and the level of 2-5 adenylate synthetase in the pellets obtained from each animal was assessed.
• Figure 7 is a graph depicting the IgG anti-FLUZONE titer in Rhesus monkeys administered anti-CTLA4 antibody.
• Serum anti-FLUZONE IgG titers were assessed for animals in Group 1 (open triangle; administered FLUZONE on weeks 0 and 4 and administered anti-CTLA4 antibody on week 0), Group 2 (open square; administered FLUZONE on weeks 0 and 4 and administered an irrelevant human anti-KLH antibody on week 0), Group 3 (closed circle; administered FLUZONE on weeks 0 and 4 and administered anti-CTLA4 antibody on week 4), Group 4 (open circle; administered FLUZONE on weeks 0 and 4 and administered an irrelevant human anti-KLH antibody on week 4) and Group 5 (closed triangle; administered FLUZONE on weeks 0 and 4 but no antibody was administered).
• FLUZONE was administered IM and antibodies were administered IV at 5 mg/kg.
• Anti-FLUZONE IgG titers were assessed one week before immunization with FLUZONE (week -1, also referred to as "prebleed") and then at week 0, week 2, week 4, week 6 and week 8.
• Animals in Group 3 (immunized with FLUZONE on weeks 0 and 4 and administered anti-CTLA4 antibody on week 4) demonstrated increased anti-FLUZONE IgG serum titers compared with animals in the other groups.
• Figure 8 is a graph depicting the anti-FLUZONE IgG serum titer in Rhesus monkeys immunized with FLUZONE and on weeks 0 and 4 and administered anti-CLTA4 antibody on week 0 (Group 1), immunized with FLUZONE on weeks 0 and 4 and administered an irrelevant antibody on week 0 (Group 2), immunized with FLUZONE on weeks 0 and 4 and administered anti-CTLA4 antibody on week 4 (Group 3), immunized with FLUZONE on weeks 0 and 4 and administered an irrelevant antibody on week 0 (Group 4), and immunized with FLUZONE on weeks 0 and 4 (Group 5).
• FIG. 9 is a bar graph depicting the anti-FLUZONE IgG antibody titers at week 6 in
• Rhesus monkeys immunized with FLUZONE on weeks 0 and 4 (Groups 1-5).
• an element means one element or more than one element.
• a “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain R group with similar chemical properties (e.g., charge or hydrophobicity).
• a conservative amino acid substitution will not substantially change the functional properties of a protein.
• the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson, Methods MoI. Biol. 243:307-31 (1994).
• Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine.
• Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine- tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine.
• a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256:1443-45 (1992), herein incorporated by reference.
• a “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
• Preferred amino acid substitutions are those which: (1 ) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, and (4) confer or modify other physicochemical or functional properties of such analogs.
• Analogs comprising substitutions, deletions, and/or insertions can include various muteins of a sequence other than the specified peptide sequence.
• single or multiple amino acid substitutions may be made in the specified sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts, e.g., outside of the CDRs).
• a conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence).
• Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al., Nature 354:105 (1991), which are each incorporated herein by reference.
• Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions.
• Genetics Computer Group (GCG available from Genetics Computer Group, Inc.), also referred to as the Wisconsin Package, is an integrated software package of over 130 programs for accessing, analyzing and manipulating nucleotide and protein sequences. GCG contains programs such as "Gap” and "Bestfit” which can be used with default parameters to determine sequence similarity, homology and/or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG version 6.1, version 7.0, version 9.1 , and version 10.0.
• Polypeptide sequences also can be compared using FASTA, a program in GCG, using default or recommended parameters.
• FASTA e.g., FASTA2 and FASTA3
• FASTA2 and FASTA3 provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson, Methods Enzymol. 183:63-98 (1990); Pearson, Methods MoI. Biol. 132:185-219 (2000)).
• Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn, using default parameters. See, e.g., Altschul et al., J. MoI. Biol. 215:403-410 (1990); Altschul et al., Nucleic Acids Res. 25:3389-402 (1997); herein incorporated by reference.
• An intact "antibody” comprises at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (incorporated by reference in its entirety for all purposes).
• Each heavy chain is comprised of a heavy chain variable region (HCVR or V H ) and a heavy chain constant region (C H ).
• the heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3.
• Each light chain is comprised of a light chain variable region (LCVR or VL) and a light chain constant region.
• the light chain constant region is comprised of one domain, C L .
• VH and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
• CDR complementarity determining regions
• FR framework regions
• Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
• the assignment of amino acids to each domain is in accordance with the definitions of Kabat, Sequences of Proteins of lmmunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)), or Chothia & Lesk, J. MoI. Biol. 196:901-917 (1987); Chothia et al., Nature 342:878-883 (1989).
• antibody portion refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., CTLA4). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
• binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, C L and CH 1 domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (Hi) a Fd fragment consisting of the V ⁇ and CH1 domains; (iv) a Fv fragment consisting of the V L and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a V H domain; and (vi) an isolated complementarity determining region (CDR).
• a Fab fragment a monovalent fragment consisting of the VL, VH, C L and CH 1 domains
• F(ab') 2 fragment a bivalent fragment comprising two Fab fragments linked by a dis
• the two domains of the Fv fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (known as single chain Fv (scFv)); see e.g., Bird et al. Science 242:423-426 (1988) and Huston et al. Proc. Natl. Acad. ScL USA 85:5879-5883 (1988)).
• single chain Fv single chain Fv
• Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
• Other forms of single chain antibodies, such as diabodies are also encompassed.
• Diabodies are bivalent, bispecific antibodies in which V H and V L domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger et al. Proc. Natl. Acad. ScL USA 90:6444-6448 (1993); Poljak et al. Structure 2:1121-1123 (1994)).
• an antibody or antigen-binding portion thereof may be part of larger immunoadhesion molecules, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides.
• immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov et al. Human Antibodies and Hybridomas 6:93-101 (1995)) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov et al. MoI. Immunol. 31:1047-1058 (1994)).
• CDRs from an antibody are incorporated into a molecule either covalently or noncovalently to make it an immunoadhesin that specifically binds to an antigen of interest, such as CTLA4.
• the CDR(s) may be incorporated as part of a larger polypeptide chain, may be covalently linked to another polypeptide chain, or may be incorporated noncovalently.
• Antibody portions, such as Fab and F(ab') 2 fragments can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies.
• antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.
• an antigen-binding portion thereof may also be used.
• An antigen- binding portion competes with the intact antibody for specific binding. See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, N.Y. (1989)) (incorporated by reference in its entirety for all purposes).
• Antigen-binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies.
• antigen-binding portions include Fab, Fab', F(ab') 2, Fd, Fv, dAb, and complementarity determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies, diabodies and polypeptides that contain at least a portion of an antibody that is sufficient to confer specific antigen binding to the polypeptide.
• the binding sites may be identical to one another or may be different.
• human antibody or “human sequence antibody”, as used interchangeably herein, include antibodies having variable and constant regions (if present) derived from human germline immunoglobulin sequences.
• the human sequence antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
• human antibody as used herein, is not intended to include “chimeric” antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences (i.e., "humanized” or PRI MATIZED TM antibodies).
• chimeric antibody as used herein means an antibody that comprises regions from two or more different antibodies.
• one or more of the CDRs are derived from a human anti-CTLA4 antibody.
• all of the CDRs are derived from a human anti-CTLA4 antibody.
• the CDRs from more than one human anti-CTLA4 antibodies are combined in a chimeric human antibody.
• a chimeric antibody may comprise a CDR1 from the light chain of a first human anti- CD40 antibody, a CDR2 from the light chain of a second human anti-CTLA4 antibody and a CDR3 and CDR3 from the light chain of a third human anti-CTLA4 antibody, and the CDRs from the heavy chain may be derived from one or more other anti-CD40 antibodies.
• the framework regions may be derived from one of the same anti-CTLA4 antibodies or from one or more different human(s).
• chimeric antibody includes an antibody comprising a portion derived from the germline sequences of more than one species.
• "Glycoform” refers to a complex oligosaccharide structure comprising linkages of various carbohydrate units. Such structures are described in, e.g., Essentials of Glycobiology Varki et al., eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1999), which also provides a review of standard glycobiology nomenclature. Such glycoforms include, but are not limited to, G2, G1 , GO, G-1 , and G-2 (see, e.g., International Patent Publication No. WO 99/22764).
• glycosylation pattern is defined as the pattern of carbohydrate units that are covalently attached to a protein (e.g., the glycoform) as well as to the site(s) to which the glycoform(s) are covalently attached to the peptide backbone of a protein, more specifically to an immunoglobulin protein. It is likely that antibodies expressed by different cell lines or in transgenic animals will have different glycoforms and/or glycosylation patterns compared with each other. However, all antibodies encoded by the nucleic acid molecules provided herein, or comprising the amino acid sequences provided herein are part of the instant invention, regardless of the glycosylation of the antibodies.
• an effective amount is meant an amount that when administered to a mammal, preferably a human, mediates a detectable therapeutic response compared to the response detected in the absence of the compound.
• a therapeutic response such as, but not limited to, inhibition of and/or decreased tumor growth, tumor size, metastasis, and the like, can be readily assessed by a plethora of art-recognized methods, including, e.g., such methods as disclosed herein.
• the effective amount of the compound or composition administered herein varies and can be readily determined based on a number of factors such as the disease or condition being treated, the stage of the disease, the age and health and physical condition of the mammal being treated, the severity of the disease, the particular compound being administered, and the like.
• Compet By the term “compete”, as used herein with regard to an antibody, is meant that a first antibody, or an antigen-binding portion thereof, competes for binding with a second antibody, or an antigen-binding portion thereof, where 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-compete" with each other for binding of their respective epitope(s).
• cross-competing antibodies can bind to the epitope, or potion of the epitope, to which the antibodies used in the invention bind. Use of both competing and cross-competing antibodies is encompassed by the present invention.
• epitope includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor.
• Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
• "Instructional material,” as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the compound, combination, and/or composition of the invention in the kit for affecting, alleviating or treating the various diseases or disorders recited herein.
• the instructional material can describe one or more methods of alleviating the diseases or disorders in a cell, a tissue, or a mammal, including as disclosed elsewhere herein.
• the instructional material of the kit may, for example, be affixed to a container that contains the compound and/or composition of the invention or be shipped together with a container which contains the compound and/or composition.
• the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the compound cooperatively.
• patient refers to a human.
• Conventional notation is used herein to portray polypeptide sequences: the left-hand end of a polypeptide sequence is the amino-terminus; the right-hand end of a polypeptide sequence is the carboxyl-terminus.
• telomere binding binds a compound, e.g., a protein, a nucleic acid, an antibody, and the like, which recognizes and binds a specific molecule, but does not substantially recognize or bind other molecules in a sample.
• an antibody or a peptide inhibitor which recognizes and binds a cognate ligand (e.g., an anti-CTLA4 antibody that binds with its cognate antigen, CTLA4) in a sample, but does not substantially recognize or bind other molecules in the sample.
• the specified binding moiety binds preferentially to a particular target molecule and does not bind in a significant amount to other components present in a test sample.
• a variety of assay formats may be used to select an antibody that specifically binds a molecule of interest. For example, solid- phase ELISA immunoassay, immunoprecipitation, BIAcore, FACS, and Western blot analysis are among many assays that may be used to identify an antibody that specifically reacts with CTLA4.
• a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times background, even more specifically, an antibody is said to "specifically bind" an antigen when the equilibrium dissociation constant (K D ) is ⁇ 1 ⁇ M, preferably ⁇ 100 nM and most preferably ⁇ 10 nM.
• K D equilibrium dissociation constant
• K 0 refers to the equilibrium dissociation constant of a particular antibody- antigen interaction.
• substantially pure means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species (e.g., an anti-CTLA4 antibody) comprises at least about 50 percent (on a molar basis) of all macromolecular species present.
• a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, more preferably more than about 85%, 90%, 95%, and 99%.
• the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
• to "treat” means reducing the frequency with which symptoms of a disease (i.e., tumor growth and/or metastasis, or other effect mediated by the numbers and/or activity of immune cells, and the like) are experienced by a patient.
• the term includes the administration of the compounds or agents of the present invention to prevent or delay the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder.
• Treatment may be prophylactic (to prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease.
• “Combination therapy” embraces the administration of an immunostimulatory anti-
• CTLA4 antibody preferably, CP-675,206
• another therapeutic agent as part of a specific treatment regimen optionally including a maintenance phase, intended to provide a beneficial effect from the co-action of these therapeutic agents.
• the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
• Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
• “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
• Combination therapy embraces administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues.
• the therapeutic agents can be administered by the same route or by different routes.
• a first therapeutic agent e.g., a chemotherapeutic agent
• a second agent e.g., anti- CTLA4 antibody
• a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
• both the therapeutic agents may be administered by intravenous or subcutaneous injection.
• sequential means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of an anti-CTLA4 antibody and a chemotherapeutic agent, a sequential dosage regimen could include administration of the anti-CTLA4 antibody before, simultaneously, substantially simultaneously, or after administration of the chemotherapeutic agent, but both agents will be administered in a regular sequence or order.
• sequential dosage regimen means, unless otherwise specified, to keep apart one from the other.
• simultaneous means, unless otherwise specified, happening or done at the same time, i.e., the compounds of the invention are administered at the same time.
• substantially simultaneously means that the compounds are administered within minutes of each other (e.g., within 10 minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two compounds separately).
• concurrent administration and substantially simultaneous administration are used interchangeably.
• Sequential administration refers to temporally separated administration of the anti-CTLA4 antibody and the chemotherapeutic agent.
• Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent, a dendritic cell vaccine or other tumor vaccine) and non-drug therapies (such as, but not limited to, surgery or radiation treatment).
• the combination therapy further comprises radiation treatment
• the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
• adjuvant therapy refers to treatment given after the primary treatment, including, without limitation, radiation, chemotherapy, hormone therapy, etc.
• the goal of adjuvant therapy is to increase the patients' chances of remission or cure, to increase the patients' overall survival benefit, and to help decrease the risk of recurrence. Therefore, it will be understood that if the anti-CTLA4 antibody and therapeutic agent combination is administered as adjuvant therapy, the combination may be administered to the patient after the primary treatment, e.g., the patient is given a regimen of surgery, radiation and/or chemotherapy, followed by a course of a combination of an anti-CTLA4 antibody and a therapeutic agent.
• the dose of anti-CTLA4 antibody and therapeutic agent may be considered a therapeutic dose or a maintenance dose, depending on the goals of the adjuvant therapy.
• the term "neoadjuvant therapy" refers to treatment given before the primary treatment, including, without limitation, surgery, radiation, chemotherapy, etc. In the neoadjuvant setting, the dose of anti-CTLA4 antibody and therapeutic agent is considered a therapeutic dose.
• first-line therapy refers to the first type of therapy given for a condition or disease, or the first therapy of choice for the treatment of a particular type of cancer. It necessarily follows that the term “second-line therapy” therefore refers to the treatment given when the initial or first-line therapy is unsuccessful, and “third-line therapy” refers to a treatment or treatment regimen that is given when both the initial treatment and the subsequent treatment are unsuccessful.
• CTLA4 antibodies described herein can be used to treat a wide variety of cancers.
• administration of a therapeutic agent, when administered with an immunoenhancing anti-CTLA4 antibody may provide a synergistic effect.
• the agent that mediates an anti-tumor effect may mediate a decrease in tumor load, may mediate an increase of tumor antigens in the host antigen-presentation route, may decrease inflammation such that the antibody and/or other therapeutic agents may better penetrate the tumor, and/or may mediate a decrease in immune-suppressive tumor factors.
• the combination of an anti- CTLA4 antibody and at least one therapeutic agent may mediate a synergistic therapeutic effect thereby providing a benefit to a patient in need thereof which is greater than either compound alone.
• Cancers that may be treated include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, Kaposi's sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, erythroblastoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, a primary or secondary brain tumor, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, skin cancer, bone cancer, cancer of the small intestine, cancer of the anal region, cancer of the head or neck, gastrointestinal (gastric, colorectal, and duodenal) cancer, e
• the cancers include non-Hodgkin's lymphoma, non-small cell lung cancer, colorectal carcinoma, chronic myeloid leukemia, chronic lymphocytic leukemia, pancreatic cancer, breast cancer and ovarian cancer.
• Non-Hodgkin's lymphoma includes administering CP-675,206 to treat NHL, in combination with at least one therapeutic agent, preferably, rituximab (RITUXAN; Genentech, San Francisco, CA).
• at least one therapeutic agent preferably, rituximab (RITUXAN; Genentech, San Francisco, CA).
• the combination can be administered to treat a patient afflicted with indolent NHL or aggressive NHL.
• the NHL is indolent NHL
• the combination of CP- 675,206 and rituximab comprises first-line therapy.
• the combination therapy is administered as second-line therapy following cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and/or CHOP-R (cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab).
• the combination is followed by administration of rituximab as a single agent (SA) therapy.
• SA single agent
• the combination of rituximab and CP-675,206 may increase and/or prolong an anti-tumor cell response thereby providing a therapeutic benefit to a patient suffering from NHL.
• a combination of CP-675,206 and rituximab is administered as a second-line therapy to treat aggressive NHL refractory to CHOP-R.
• the method further comprises administering rituximab as a single agent therapy following administration of the CP-675,206/rituximab combination.
• the combination of CP-675,206 and rituximab is administered to a patient as a second-line therapy following another treatment including, but not limited to, a chemotherapeutic therapy or a bone marrow transplant.
• the CP-675,206 rituximab combination is administered following high-dose bone marrow ablative chemotherapy and bone marrow transplant (BMT).
• the combination is administered as a first-line therapy prior to bone marrow ablation chemotherapy and BMT.
• NSCLC Non-small cell lung cancer
• the invention includes a method for treating NSCLC comprising administering a combination comprising CP-675,206 and a therapeutic agent to a patient in need of treatment.
• the agent is a non-immunesuppressive chemotherapeutic agent, such as, but not limited to, gefitinib (IRESSA).
• IRESSA gefitinib
• the combination of CP-675,206 and therapeutic agent may increase the immune response to the tumor due to, inter alia, increased release of tumor antigen associated with the cytotoxic effect of the chemotherapeutic agent.
• any therapeutic agent that mediates cell death and/or release of tumor antigen can be used with an anti-CTLA4 antibody to provide an increased immune response to the tumor and, thereby, providing a therapeutic benefit to the patient.
• the skilled artisan would further understand once armed with the teachings provided herein, that the therapeutic effect can be further enhanced wherein the therapeutic agent does not decrease the immune enhancing effect of the antibody.
• gefitinib is a chemotherapeutic agent known not to decrease the immune response in a patient
• the invention is not limited to this, or any other, particular therapeutic agent. Rather, in an embodiment, the invention encompasses administration of CP-675,206 and a therapeutic agent that may mediate a therapeutic response to a NSCLC tumor.
• treatment comprises administration combination therapy comprising CP-675,206 and platinum-based chemotherapy.
• CP- 675,206 is administered to a NSCLC patient following a course of platinum-based therapy as an adjuvant therapy. That is, a patient that has been administered a course of platinum- based therapy and where the disease has responded or remained stable is administered CP- 675,206.
• the patient NSCLC is Stage MIb (with effusion) or Stage IV disease that has responded or remained stable after about six cycles of a platinum-containing regimen.
• the patient is administered CP-675,206 at least about three weeks after the last dose of platinum-based chemotherapy.
• CP- 675,206 is administered within about six weeks after the last dose of platinum-based chemotherapy. In another aspect, CP-675,206 is administered at least about three weeks after but within six weeks of the last dose of platinum-based therapy.
• platinum-based chemotherapy comprises a platinum-based compound selected from such compounds as cisplatin, carboplatin (PARAPLATIN), eptaplatin, lobaplatin, nedaplatin, oxaliplatin (ELOXATIN, Sanofi), streptozocin, satraplatin (JM-126).
• treatment for lung cancer comprises administration of bevacizumab (AVASTIN) and CP-675,206.
• the lung cancer comprises non-small cell and small cell lung cancer.
• the lung cancer comprises small cell lung cancer.
• the cancer is NSCLC and the treatment encompasses administration of CP-675,206 in combination with a taxane, where a taxane can include, but is not limited to, docetaxel (TAXOTERE), and paclitaxel (TAXOL), in further combination with gemcitabine (GEMZAR).
• a taxane can include, but is not limited to, docetaxel (TAXOTERE), and paclitaxel (TAXOL), in further combination with gemcitabine (GEMZAR).
• the invention encompasses a method for treating NSCLC comprising administration of a CP-675,206, a taxane (e.g., docetaxel and paclitaxel), and a platinum compound.
• the method for treating NSCLC is a first line therapy comprising administering a combination of CP-675,206, a taxane and a platinum compound where the taxane is paclitaxel and the platin is carboplatin (carbo/paclitaxel).
• the combination of CP-675,206, paclitaxel and carboplatin is administered contemporaneously, or in sequence.
• the paclitaxel/carboplatin combination is administered prior to or following administration of CP-675,206. That is, the antibody is contemporaneously administered in combination with the carbo/paclitaxel therapy or it is administered following carbo/paclitaxel therapy.
• the interval between administration of carbo/paclitaxel therapy and administration of the antibody may be readily determined by one skilled in the art based upon well-known methods.
• the cancer is locally advanced Stage INb NSCLC.
• the NSCLC is metastatic Stage IV NSCLC.
• the CP-675,206-carboplatin-paclitaxel combination is administered with bevacizumab.
• the CP-675,206-carboplatin-paclitaxel combination is administered with sunitinib (SU11248).
• the CP-675,206-carboplatin- paclitaxel combination is administered with PF03512676 (CpG-7909).
• the therapy is administration of docetaxel
• CP-675,206 as second line therapy for NSCLC for patients with locally advanced Stage IHb or metastatic Stage IV disease after failure of prior platinum-based chemotherapy.
• CP-675,206 is administered contemporaneously with docetaxel therapy.
• CP-675,206 is administered following docetaxel therapy.
• the NSCLC comprises locally advanced Stage HIb or metastatic Stage IV non-small cell lung cancer after failure of prior platinum-based chemotherapy.
• the invention includes treatment for NSCLC where the therapy comprises administration of CP-675,206 and erlotinib (TARCEVA) as second line therapy.
• CP-675,206 is contemporaneously administered with erlotinib.
• CP-675,206 is administered following erlotinib therapy.
• the invention includes a second line therapy for NSCLC comprising administration of CP-675,206 and pemetrexed (ALIMTA).
• CP- 675,206 is administered contemporaneously with pemetrexed.
• CP- 675,206 is administered following pemetrexed therapy.
• the NSCLC is locally advanced Stage IHb.
• the NSCLC is metastatic Stage IV non- small cell lung cancer after failure of prior platinum-based chemotherapy.
• the invention includes treatment of locally advanced Stage
• CP-675,206 is administered as a single agent. In another aspect, CP-675,206 is administered in combination with a therapeutic agent.
• the invention includes a method for treating cancer of the colon and/or rectum.
• the method comprises administering a combination comprising CP-675,206 and fluorouracil (5FU) as first line therapy for CRC patients as first line therapy of CRC patients intolerant of oxaliplatin (ELOXATIN) or irinotecan (CAMPTO).
• the treatment comprises administering a combination of CP-675,206 and capecitabine (XELODA) as first line therapy for patients intolerant of oxaliplatin or irinotecan.
• the therapy comprises first line treatment of patients with metastatic carcinoma of the colon or rectum comprising administration of CP-675,206 and
• FOLFOX fluorouracil, leucovorin, and oxaliplatin.
• CP-675,206 is administered contemporaneously with FOLFOX therapy.
• CP-675,206 is administered following FOLFOX therapy.
• the treatment comprises adjuvant therapy of patients with Stage III colon cancer who have undergone complete resection of the primary tumor.
• the therapy comprises administration of CP-675,206 and FOLFOX (fluorouracil, leucovorin, and oxaliplatin).
• CP-675,206 is administered contemporaneously with FOLFOX therapy.
• CP-675,206 is administered following FOLFOX therapy.
• the therapy comprises first line treatment of patients with metastatic CRC comprising administration of CP-675,206 and FOLFIRI (fluorouracil, leucovorin, and irinotecan).
• CP-675,206 is administered contemporaneously with FOLFIRI therapy.
• CP-675,206 is administered following FOLFIRI therapy.
• the therapy comprises treatment of CRC comprising administration of CP-675,206 and cetuximab (ERBITUX, ImClone).
• CP-675,206 is administered contemporaneously with cetuximab.
• CP- 675,206 is administered following cetuximab.
• the invention encompasses a method of treating CRC comprising administering a combination of CP-675,206 and fluorouracil and capecitabine as adjuvant therapy.
• a chemotherapeutic agent which can mediate increased release of a tumor antigen
• CP-675,206 may mediate an increased immune response to the tumor thereby providing a therapeutic benefit to a patient afflicted therewith.
• the invention includes a method of treating chronic myeloid leukemia (CML).
• the method comprises administering a combination of CP- 675,206 and imatinib mesylate (GLEEVEC, Novartis) as first line therapy of CML.
• GLEEVEC imatinib mesylate
• the invention includes a method for treating chronic lymphocytic leukemia (CLL).
• CLL chronic lymphocytic leukemia
• the treatment comprises administration of CP- 675,206 and imatinib mesylate as first line therapy. 5.
• the invention includes a method for treating pancreatic cancer comprising administering a combination of CP-675,206 and gemcitabine (GEMZAR).
• the therapy is a first line treatment for patients with locally advanced (non-resectable
• Stage Il or Stage III adenocarcinoma of the pancreas.
• the cancer is metastatic (Stage IV) adenocarcinoma of the pancreas.
• gemcitabine is administered contemporaneously with CP-675,206.
• CP-675,206 is administered following administration of gemcitabine.
• CP-675,206 is administered after at least one course of gemcitabine.
• gemcitabine is administered intravenously at a dose of about 1000 mg/m 2 once per week for up to seven (7) weeks or until toxicity necessitates reducing or withholding a dose.
• the administration phase is followed by a one week resting period during which gemcitabine is not administered.
• Subsequent cycles of gemcitabine administration consist of i.v. infusions once weekly for three consecutive weeks followed by one week resting period.
• CP-675,206 is administered after a full course (Ae., seven weeks administration and one week resting period) of gemcitabine.
• CP-675,206 is administered every three weeks thereafter.
• the combination of gemcitabine (e.g., three weeks administration followed by one week rest) and CP-675,206 is continued until disease progression or intolerable toxicity. 6.
• the invention includes a method to treat locally advanced or metastatic triple receptor negative breast cancer.
• the method is a first line therapy.
• the therapy comprises administering CP-675,206 and a taxane (e.g., docetaxel and paclitaxel).
• CP-675,206 taxane are administered contemporaneously.
• CP-675,206 is administered following administration of the taxane.
• the therapy comprises adjuvant treatment for breast cancer comprising administration of CP-675,206 and cyclophosphamide, doxorubicin and a taxane.
• the therapy comprises adjuvant therapy.
• therapy comprises administration of CP-675,206 and tamoxifen (NOVALDEX), anastrazole (ARIMIDEX), letrozole (FEMARA), exemestane (AROMASIN), or fulvestrant (FASLODEX), or a combination thereof.
• the therapy is adjuvant therapy for metastatic breast cancer.
• the therapy for breast cancer comprises administration of CP-675,206 and trastuzumab (HERCEPTIN).
• the antibodies are administered contemporaneously.
• trastuzumab is administered followed by administration of CP-675,206.
• the CP-675,206- trastuzumab combination therapy comprises adjuvant therapy and first line therapy for metastatic breast cancer.
• the therapy comprises administering CP-675,206 and bevacizumab.
• CP-675,206 and bevacizumab are administered contemporaneously.
• CP-675,206 is administered following administration of bevacizumab.
• the therapy for treating breast cancer comprises administering CP-675,206 and cetuximab.
• CP-675,206 and cetuximab are administered contemporaneously.
• CP-675,206 is administered following administration of cetuximab.
• the therapy for treating breast cancer comprises administering CP-675,206 and axitinib.
• CP-675,206 and axitinib are administered contemporaneously.
• CP-675,206 is administered following administration of axitinib.
• the invention includes a method for treatment carcinoma of the ovary.
• therapy comprises administration of CP-675,206 and carboplatin and paclitaxel.
• CP-675,206 is administered contemporaneously with carboplatin and paclitaxel.
• CP-675,206 is administered following administration of carboplatin and paclitaxel.
• the treatment is a first line treatment for advanced carcinoma of the ovary.
• therapy comprises second line treatment for patients who have progressed (e.g., as indicated by tumor assessment, CA-125 doubling value, CT scan, and the like) following paclitaxel-based therapy.
• therapy comprises administration of CP-675,206 as a single agent.
• therapy comprises administration of CP-675,206 in combination with an agent selected from the group consisting of altretamine, anastrozole, bevacizumab, carboplatin, cisplatin, cyclophosphamide, liposomal doxorubicin, docetaxel, gemcitabine, ifosfamide, irinotecan, letrozole, melphalan, oral etoposide, oxaliplatin, tamoxifen, topotecan, and vinorelbine, and any combination thereof.
• an agent selected from the group consisting of altretamine, anastrozole, bevacizumab, carboplatin, cisplatin, cyclophosphamide, liposomal doxorubicin, docetaxel, gemcitabine, ifosfamide, irinotecan, letrozole, melphalan, oral etoposide, oxaliplatin, tamoxifen,
• the treatment comprises gastric cancer and therapy comprises administering CP-675,206 and irinotecan.
• CP-675,206 and irinotecan are administered contemporaneously.
• CP-675,206 is administered following administration of irinotecan.
• treatment comprises administration of CP-675,206, fluorouracil and leucovorin.
• CP-675,206, fluorouracil and leucovorin are administered contemporaneously.
• CP-675,206 is administered following administration of fluorouracil and leucovorin.
• the cancer is liver cancer and therapy comprises administering CP-675,206 and doxorubicin, ifosfamide and vincristine.
• doxorubicin, ifosfamide and vincristine are administered contemporaneously.
• CP-675,206 is administered following administration of doxorubicin, ifosfamide and vincristine.
• the cancer is liver cancer and therapy comprises administering CP-675,206, doxorubicin, and vincristine.
• CP-675,206, and doxorubicin, ifosfamide and vincristine are administered contemporaneously.
• CP-675,206 is administered following administration of doxorubicin and vincristine. 10.
• CP-675,206 is administered to treat metastases where the metastases is to the brain and/or bone metastasis.
• the brain and bone metastases are treated using CP-675,206 regardless of the site of the primary tumor from which the cancer metastasized.
• brain metastases are treated using a combination of surgical resection and/or radiotherapeutic ablation in further combination with an anti-CTLA4 antibody, preferably, CP-675,206. That is, where multiple metastases and/or lesions greater than about 3 centimeters in diameter are present, whole brain radiation may be administered followed by administration of anti-CTLA4 antibody.
• the antibody is administered preceding radiation.
• the antibody is administered at least about 3 mg/kg, more preferably, at least about 6 mg/kg, even more preferably, at least about 10 mg/kg, and more preferably, at least about 15 mg/kg.
• the antibody is administered every three weeks, more preferably, every four weeks, and even more preferably, every three months.
• stereotactic radiosurgery is administered followed by administration of anti-CTLA4 antibody.
• the antibody is administered before SRS.
• the antibody is administered before and after SRS.
• whole brain radiation and SRS may be combined in any order to treat brain metastases, which treatment is further combined with antibody therapy.
• the antibody therapy is administered after radiation/surgery/SRS.
• antibody surgery is administered before radiation/surgery/SRS and may be administered before and after such therapy.
• brain metastases are common in melanoma.
• SRS may achieve local control of the brain metastases, most patients die of systemic metastases and/or reseeding of the CNS occurs due to poor management of the systemic disease.
• the invention provides a combination therapy to control the local brain metastases and to prevent reseeding of the CNS and control the systemic disease thereby providing a therapeutic benefit to a patient in need thereof.
• CP-675,206 is administered in combination with BCG to treat bladder cancer.
• CP-675,206 and BCG are administered contemporaneously.
• CP-675,206 is administered following administration of BCG.
• treatment of bladder cancer comprises administering CP-
• CP-675,206 and gemcitabine and cisplatin are administered contemporaneously.
• CP-675,206 is administered following administration of gemcitabine and cisplatin.
• CP-675,206 and interferon alpha are administered contemporaneously.
• CP-675,206 is administered following administration of interferon alpha.
• interferon alpha is administered as a high dose.
• treatment for multiple myeloma comprises administration of CP-675,206 and bortezomib.
• CP-675,206 and bortezomib are administered contemporaneously.
• CP-675,206 is administered following administration of bortezomib.
• therapy comprises administration of CP-675,206 and dexamethasone and thalidomide.
• CP-675,206, dexamethasone and thalidomide are administered contemporaneously.
• CP-675,206 is administered following administration of dexamethasone and thalidomide.
• anti-CTLA4 antibodies other than CP-675,206 may be used in the methods of the invention.
• Alternate antibodies are described herein, including the antibodies described in U.S. Patent Application No. 09/472,087, now issued as U.S. Patent No. 6,682,736; Int. Appl. No. PCT/US99/30895 (published June 29, 2000, as WO 00/37504); U.S. Pat. Appl. No. 10/612,497 (published November 18, 2004, as US 2004/0228858); U.S. Pat. Appl. No. 10/776,649 (published November 18, 2004, as US 2004/0228861); Int. Appl. No. Int. Appl. No.
• PCT/USOO/23356 (published March 1 , 2001, as WO 01/14424) (e.g., antibody 10D1 , also known as MDX-010, and referred to herein as ipilimumab, Medarex, Princeton, NJ); Int. Appl. No. PCT/US99/28739 (published June 8, 2000, as WO 00/32231); U.S. Pat. Nos. 5,811,097, 5,855,887, 6,051 ,227, and 6,207,156; U.S. Pat. No. 5,844,095, to Linsley et al.; Int. Appl. No. PCT/US92/05202 (published Jan.
• the antibodies are described in U.S. Patent No. 6,682,736, and WO 01/14424. Even more preferably, the antibodies include an antibody having the heavy and light chain amino acid sequences of an antibody selected from the group consisting of 4.1.1 , 4.8.1 , 4.10.2, 4.13.1, 4.14.3, 6.1.1 , 11.2.1 (CP-675,206 or ticilimumab), 11.6.1 , 11.7.1., 12.3.1.1, 12.9.1.1, and ipilimumab. B.
• the present invention encompasses administration of anti-CTLA4 antibody in combination with standard of care therapy to treat a variety of pathogen-associated diseases, disorders or conditions, where an immune response to the pathogen would provide a therapeutic benefit. These include, but are not limited to, bacterial, viral, fungal, parasitic, and other pathogenic disease. Treatment of infectious disease comprising anti-CTLA4 antibody blockade is discussed in, e.g., WO 03/086459, published on Oct. 23, 2003.
• anti-CTLA4 antibody blockade can be used in combination with vaccines and other therapeutic agents, including standard of care therapy, to treat a disease, disorder or condition associated with a pathogens, or a toxin derived therefrom. That is, previous studies have demonstrated that anti-CTLA4 antibody blockade can be useful in treatment of infectious parasites (McCoy et al., J. Exp. Med. 186:183-187 (1997); Murphy et al., J. Immunol. 161 :4153-4160 (1998)).
• pathogens for which this therapeutic approach may be particularly useful, include, but are not limited to HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas aureginosa, and Helicobacter pylori.
• viruses treatable by methods of the invention include hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1 , HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, ebola virus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, poxvirus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
• herpes virus e.g., VZV, HSV-1 , HAV-6, HSV-II, and CMV, Epstein Barr virus
• adenovirus e.g., adenovirus
• influenza virus flaviviruses
• bacterial infection treatable by methods of the invention include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, helicobacter, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme Disease bacteria (e.g., Borrelia burgdorferi).
• fungal infection treatable according to the methods of the invention include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
• Candida albicans, krusei, glabrata, tropicalis, etc.
• Cryptococcus neoformans Aspergillus (fumigatus, niger, etc.)
• Genus Mucorales micor, absidia, rhizophus
• Sporothrix schenkii Blastomyces dermatitidis
• Paracoccidioides brasiliensis Coccidioides
• parasitic infection treatable by methods of the invention include, among others, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis. 1.
• CTLA4 blockade may be useful for treatment of viral disease, more specifically, studies in rhesus macaques demonstrated that anti-CTLA4 (i.e., ipilimumab), combined with antiretroviral therapy ("ART"), was associated with increased antiviral response. See Hryniewicz et al., Blood 108:3834-3842 (2006).
• CTLA4 blockade not only decreased viral load and increased virus-specific effector T cells, it also decreased the level of immunosuppressive molecules (e.g., transforming growth factor beta [TGF- ⁇ ] and indoleamine 2,3-dioxygenase [IDO]), in SIV mac25 i-infected macaques also receiving ART (didanosine, stavudine and tenofovir [PMPA]).
• immunosuppressive molecules e.g., transforming growth factor beta [TGF- ⁇ ] and indoleamine 2,3-dioxygenase [IDO]
• TGF- ⁇ transforming growth factor beta
• IDO indoleamine 2,3-dioxygenase
• PMPA tenofovir
• anti-CTLA4 antibodies in particular CP-675,206, and their pharmaceutically acceptable salts, solvates and derivatives, may be administered alone or as part of a combination therapy.
• embodiments comprising co-administration of, and compositions which contain, in addition to a compound of the invention, one or more additional therapeutic agents.
• Such multiple drug regimens often referred to as combination therapy, may be used in the treatment and prevention of infection and multiplication of the human immunodeficiency virus, HIV, and related pathogenic retroviruses within a patient in need of treatment or one at risk of becoming such a patient.
• HAART Highly Active Anti-Retroviral Therapy
• the methods of treatment and pharmaceutical compositions of the present invention may employ a compound of the invention in the form of monotherapy, but said methods and compositions may also be used in the form of combination therapy in which anti-CTLA4 antibody is co-administered in combination with one or more additional therapeutic agents such as those described in detail further herein.
• the therapeutic agents that may be used in combination with the anti-CTLA4 antibody include, but are not limited to, those useful as HIV protease inhibitors (PIs), non- nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), CCR5 antagonists, agents which inhibit the interaction of gp120 with CD4, other agents which inhibit the entry of HIV into a target cell (such as fusion inhibitors), inhibitors of HIV integrase, RNaseH inhibitors, prenylation inhibitors, maturation inhibitors which act by interfering with production of the HIV capsid protein, compounds useful as anti-infectives, and others as described below.
• PIs HIV protease inhibitors
• NRTIs non- nucleoside reverse transcriptase inhibitors
• NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
• CCR5 antagonists agents which inhibit the interaction of gp120 with CD4,
• a combination drug treatment may comprise two or more compounds having the same, or different, mechanism of action.
• a combination may comprise a compound of the invention and: one or more NRTIs; one or more NRTIs and a Pl; one or more NRTIs and another CCR5 antagonist; a Pl; a Pl and an NNRTI; an NNRTI; and so on.
• PIs include, but are not limited to, amprenavir (141W94), CGP-73547,
• NRTIs include, but are not limited to, abacavir, GS-840, lamivudine, adefovir dipivoxil, beta-fluoro-ddA, zalcitabine, didanosine, stavudine, zidovudine, tenofovir (9-[9(R)-2-(phosphonomethoxy)propyl]adenine; PMPA), tenofovir disoproxil fumarate (Viread; Gliead Sciences), amdoxovir (DAPD), SPD-754, SPD-756, racivir, reverset (DPC-817), MIV- 210 (FLG), beta-L-Fd4C (ACH-126443), MIV-310 (alovudine, FLT), dOTC, DAPD, entecavir, GS-7340, emtricitabine (FTC).
• NNRTIs include, but are not limited to, efavirenz, HBY-097
• TMC-120 (dapivirine), TMC-125, etravirine, delavirdine, DPC-083, DPC-961 , capravirine, rilpivirine, 5- ⁇ [3,5-Diethyl-1 -(2-hydroxyethyl)-1 A7-pyrazol-4-yl]oxy ⁇ isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; GW-678248, GW-695634, MIV-150, calanolide, and tricyclic pyrimidinone derivatives as disclosed in WO 03/062238.
• CCR5 antagonists include, but are not limited to, TAK-779, SC-351125, ancriviroc (formerly known as SCH-C), vicriviroc (formerly known as SCH-D), maraviroc, NCB-9471, CCR5mAb004, PRO-140, aplaviroc (also known as GW-873140, Ono-4128, AK- 602), AMD-887 CMPD-167, methyl 1-eA7do- ⁇ 8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]- S-azabicyclop ⁇ . ⁇ oct-S-yl ⁇ -methyl ⁇ . ⁇ . ⁇ J-tetrahydro-IW-imidazo ⁇ . ⁇ -clpyridine- ⁇ - carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, methyl 3- enc/o- ⁇ 8-[(3S)-3-(acetamido)-3-(3-fluor
• the anti-CTLA4 antibody preferably CP-675,206
• anti-CTLA4 antibody/maraviroc combination therapy comprises assessing whether is expressed on the surface of the patient's cells.
• the therapy comprises assessing the co-receptor ⁇ i.e., CXCR4 or CCR5) tropism of the HIV virus to determine whether the patient is infected with an HIV that uses the CCR5 co-receptor, the CXCR4 co-receptor, or both (dual/mixed tropic) to determined whether the patient is a candidate for maraviroc therapy.
• the co-receptor tropism assay is TROFILE (Monogram Biosciences, Inc., San Francisco, CA). This is because treatment with maraviroc inhibits CCR5-mediated entry into cells. Thus, assessing CCR5 expression by a patient's cell and/or assessing the co-receptor tropism of the virus optimizes the treatment options for the patient. Examples of entry and fusion inhibitors include, but are not limited to, BMS-806,
• prenylation inhibitors include, but are not limited to, HMG CoA reductase inhibitors, such as statins (e.g., atorvastatin).
• statins e.g., atorvastatin
• maturation inhibitors include 3-O-(3'3'-dimethylsuccinyl) betulic acid (otherwise known as PA-457) and alphaHGA.
• Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• An exemplary, non limiting range for a therapeutically effective amount of ticilimumab administered according to the invention is at least about 1 mg/kg, at least about 5 mg/kg, at least about 10 mg/kg, more than about 10 mg/kg, or at least about 15 mg/kg, for example about 1-30 mg/kg, or for example about 1-25 mg/kg, or for example about 1-20 mg/kg, or for example about 5-20 mg/kg, or for example about 10-20 mg/kg, or for example about 15-20 mg/kg, or for example, about 15 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
• CP-675,206 is administered in an intravenous formulation as a sterile aqueous solution containing about 5 to 20 mg/ml of antibody, in an appropriate buffer system.
• part of the dose is administered by an intravenous bolus and the rest by infusion of the antibody formulation.
• a 0.01 mg/kg intravenous injection of the antibody may be given as a bolus, and the rest of a predetermined antibody dose may be administered by intravenous injection.
• the entire low dose is administered as a single bolus injection.
• the antibody is not administered as a bolus, but the entire amount is administered by infusion.
• a predetermined dose of the antibody may be administered, for example, over a period of about an hour and a half to about five hours.
• the present invention relates to administering a combination of an anti-CTLA4 antibody and at least one therapeutic agent.
• the antibody is CP-675,206.
• the antibody is selected from various anti-CTLA4 antibodies, including, but not limited to, ipilimumab.
• the antibody is ipilimumab and the dose is about 3 mg/kg.
• the dose of ipilimumab is at least about 10 mg/kg.
• the antibody e.g., CP-675,206, ipilimumab, and the like
• the antibody is administered approximately every three weeks, more preferably, for about four cycles followed by every three months thereafter. In one aspect of this embodiment, the antibody is administered at about 10 mg/kg.
• the combination of CP-675,206 and a therapeutic agent can be administered simultaneously or the antibody and the therapeutic agent can be administered at different times.
• the antibody is administered as a single injection and/or infusion and the therapeutic agent (e.g., gemcitabine) is administered once per day commencing before, during, or after administration of the antibody.
• the therapeutic agent e.g., gemcitabine
• the present invention is not limited to any particular dosage or administration regimen for a therapeutic agent. Rather, the optimal dose, route and regimen for administration of the antibody and the therapeutic agent can be readily determined by one of ordinary skill in the relevant art using well-known methods. For instance, a single dose or multiples doses of the antibody may be administered. Alternatively, at least one dose, or at least three, six or 12 doses may be administered.
• the doses may be administered, for example, every two weeks, every three weeks, monthly, every twenty days, every 25 days, every 28 days, every 30 days, every 40 days, every 6 weeks, every 50 days, every two months, every 70 days, every 80 days, every three months, every six months or yearly.
• the antibody is administered once every three weeks, preferably for four cycles, and then every three months thereafter.
• the second therapeutic agent can be administered daily, several times or once per day, weekly, every other week, every third week, every fourth week, monthly, every three months, every six months, once per year, or any other period that provides a therapeutic benefit to the patient as determined by the skilled practitioner.
• CP-675,206 is administered once per month. In another aspect, CP- 675,206 is administered every three months. In yet another aspect, ipilimumab is administered once per month.
• the antibody can be administered until disease progression, or intolerable toxicity, or up to 12 consecutive cycles, whichever time is shorter. The antibody can also be administered using a regimen comprising administration of a loading dose followed by a lower dose. Repeat courses of at least one, and more preferably, several cycles of antibody and a therapeutic agent can be administered to a patient that experiences a tumor recurrence who had previously derived benefit from administration of the combination of an anti-CTLA4 antibody and another therapeutic agent, or the antibody or therapeutic agent not administered in combination previously.
• a single injection comprising CP-675,206 is administered to a patient intravenously at a dose of about 3 mg/kg every twenty-eight days.
• an anti-CTLA4 antibody is administered to a patient intravenously at a dose of about 3 mg/kg, preferably, about 6 mg/kg, more preferably, about 10 mg/kg, preferably, about 15 mg/kg, every three weeks. After four administrations, the antibody is then administered every three months.
• the invention encompasses administration of an anti-CTLA4 antibody, preferably CP- 675,206, in combination with a wide plethora of agents.
• an anti-CTLA4 antibody preferably CP- 675,206
• any art-recognized dosing regimen for the agent may be used.
• Dosing regimens for chemotherapeutic and other agents described herein may be found in treatises well known in the art, including, but not limited to, Cancer: Principles and Practice of Oncology, 7th edition, DeVita, Hellman, and Rosenberg, editors, Lippincott, Williams & Wilkins, 2004, and Cancer Chemotherapy and Biotherapy Principles and Practice, 4 th edition.
• administration of many agents disclosed herein may be performed based upon the FDA- approved drug label instructions.
• label instructions are readily and publicly available from the website of the Department of Health and Sciences, U.S. Food and Drug Administration, Center for Drug Evaluation and Research website, which may be searched according to drug name or active ingredient.
• the skilled artisan would understand the dosing regimen to be used in combination therapy for various diseases comprising administration of an anti-CTLA4 antibody and a therapeutic agent.
• the dose may be adjusted as known in the art based on, among other factors, toxicity, if any, and therapeutic effectiveness.
• dosing regimens for many chemotherapeutic, and other agents related to cancer treatment are well known in the art and are described in numerous publications, including those described herein. See also International Publication No. PCT/US03/12802 (published Nov. 6, 2003, as WO 03/090686), which is incorporated by reference herein for all purposes, for a list of exemplary dosing regimens for various chemotherapeutic agents (e.g., at pages 72 through 74).
• the antibody-therapeutic agent combination can be administered as an adjuvant therapy, or it can be administered to the patient as a neoadjuvant therapy prior to surgery, radiation therapy, or any other treatment, in order to sensitize the tumor cells or to otherwise confer a therapeutic benefit to the patient.
• the combination can be administered as a first line therapy, or as a second line or third line therapy, such as, but not limited to, once previous therapy(ies) has failed.
• the combination can be administered concurrently with a first line therapy, and or at any point during therapy, following initial treatment.
• a combination of an anti-CTLA4 antibody and a therapeutic agent can provide a therapeutic benefit once a previous therapy has failed, once systemic adjuvant therapy using another therapeutic agent (e.g., temozolomide, leuprolide, paclitaxel, imatinib mesylate, gefitinib, and the like) has failed.
• another therapeutic agent e.g., temozolomide, leuprolide, paclitaxel, imatinib mesylate, gefitinib, and the like
• the invention encompasses administration of an anti-CTLA4 antibody and a therapeutic agent in combination with or following additional therapy, including, but not limited to, a different therapeutic agent (e.g., a chemotherapeutic, an antibody, an immunomodulator, a cytokine, and the like) as would be appreciated by one skilled in the art based upon the disclosure provided herein.
• a different therapeutic agent e.g., a chemotherapeutic, an antibody, an immunomodulator, a cytokine, and the like
• the invention encompasses alternate embodiments employing CTLA4 antibodies in addition to CP-675,206.
• the CTLA4 antibody comprises a heavy chain wherein the amino acid sequence of the V H comprises the amino acid sequences set forth in SEQ ID NOs:3, 15 and 27.
• the V L of the CTLA4 antibody comprises the amino acid sequences set forth in SEQ ID NOs:9, 21 and 33.
• the VH and V L regions of the antibody comprise the amino acid sequences set forth in SEQ ID NO:3 (V H 4.1.1) and SEQ ID NO:9 (V L 4.1.1), respectively; the amino acid sequences set forth in SEQ ID NO:15 (V H 4.13.1) and SEQ ID NO:21 (V L 4.13.1 ), respectively; and the amino acid sequences set forth in SEQ ID NO:27 (V H 11.2.1) and SEQ ID NO:33 (V L 11.2.1), respectively.
• the antibody is CP-675,206, which has the heavy and light chain amino acid sequences of antibody 11.2.1 (ticilimumab).
• the amino acid sequence of the heavy chain comprises the amino acid sequence encoded by a nucleic acid comprising the nucleic acid sequences set forth in SEQ ID NOs:1, 13, and 25.
• the light chain comprises the amino acid sequence encoded by a nucleic acid comprising the nucleic acid sequences set forth in SEQ ID NOs:7, 19 and 31.
• the heavy and light chains comprise the amino acid sequences encoded by nucleic acids comprising the nucleic acid sequences set forth in SEQ ID NO:1 (heavy chain 4.1.1) and SEQ ID NO:7 (light chain 4.1.1), respectively; the nucleic acid sequences set forth in SEQ ID NO: 13 (heavy chain 4.13.1) and SEQ ID NO:19 (light chain 4.13.1), respectively; and the nucleic acid sequences set forth in SEQ ID NO:25 (heavy chain 11.2.1) and SEQ ID NO:31 (light chain 11.2.1), respectively.
• the antibody can comprise a heavy chain amino acid sequence comprising human CDR amino acid sequences derived from the V H 3-30 or 3-33 gene, or conservative substitutions or somatic mutations therein. It is understood that the V H 3-33 gene encodes from FR1 through FR3 of the heavy chain variable region of an antibody molecule.
• the invention encompasses an antibody that shares at least 85%, more preferably, at least 90%, yet more preferably, at least 91 %, even more preferably, at least 94%, yet more preferably, at least 95%, more preferably, at least 97%, even more preferably, at least 98%, yet more preferably, at least 99%, and most preferably, 100% identity, with the sequence from FR1 through FR3 of an antibody selected from the group consisting of 3.1.1, 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.2.1 (CP-675,206), 11.6.1 , 11.7.1 , 12.3.1.1 , 2.9.1.1 , ipilimumab, and DP-50.
• the antibody can further comprise CDR regions in its light chain derived from the A27 or the 012 gene or it may comprise the CDR regions of an antibody selected from the group consisting of 3.1.1, 4.1.1 , 4.8.1, 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.2.1 (CP-675,206), 11.6.1, 11.7.1, 12.3.1.1 , 2.9.1.1 , ipilimumab.
• the antibody inhibits binding between CTLA4 and B7-1 , B7-2, or both.
• the antibody can inhibit binding with B7-1 with an IC 50 of about 100 nM or lower, more preferably, about 10 nM or lower, for example about 5 nM or lower, yet more preferably, about 2 nM or lower, or even more preferably, for example, about 1 nM or lower.
• the antibody can inhibit binding with B7-2 with an IC 50 of about 100 nM or lower, more preferably, 10 nM or lower, for example, even more preferably, about 5 nM or lower, yet more preferably, about 2 nM or lower, or even more preferably, about 1 nM or lower.
• the anti-CTLA4 antibody has a binding affinity for CTLA4 of about 10 "8 , or greater affinity, more preferably, about 10 "9 or greater affinity, more preferably, about 10 ⁇ 10 or greater affinity, and even more preferably, about 10 "11 or greater affinity.
• the anti-CTLA4 antibody includes an antibody that competes for binding with an antibody having heavy and light chain amino acid sequences of an antibody selected from the group consisting of 4.1.1 , 6.1.1 , 11.2.1 (CP-675,206), 4.13.1 and 4.14.3. Further, the anti- CTLA4 antibody can compete for binding with antibody ipilimumab.
• the antibody preferably cross-competes with an antibody having a heavy and light chain sequence, a variable heavy and a variable light chain sequence, and/or the heavy and light CDR sequences of antibody 4.1.1 , 4.13.1 , 4.14.3, 6.1.1. or 11.2.1 (CP-675,206).
• the antibody can bind to the epitope to which an antibody that has heavy and light chain amino acid sequences, variable sequences and/or CDR sequences, of an antibody selected from the group consisting of 4.1.1 , 4.13.1, 4.14.3, 6.1.1 , or 11.2.1 (CP-675,206) binds.
• the antibody cross-competes with an antibody having heavy and light chain sequences, or antigen-binding sequences, of MDX-D010.
• the invention is practiced using an anti-CTLA4 antibody that comprises a heavy chain comprising the amino acid sequences of CDR-1 , CDR-2, and CDR- 3, and a light chain comprising the amino acid sequences of CDR-1 , CDR-2, and CDR-3, of an antibody selected from the group consisting of 3.1.1 , 4.1.1 , 4.8.1, 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.2.1 (CP-675,206), 11.6.1 , 11.7.1, 12.3.1.1 , and 12.9.1.1 , or sequences having changes from the CDR sequences selected from the group consisting of conservative changes, wherein the conservative changes are selected from the group consisting of replacement of nonpolar residues by other nonpolar residues, replacement of polar charged residues other polar uncharged residues, replacement of polar charged residues by other polar charged residues, and substitution of structurally similar residues; non-conservative substitutions, wherein the non-conservative substitutions are selected from the group consisting of substitution of polar charged
• the antibody contains fewer than 10, 7, 5, or 3 amino acid changes from the germline sequence in the framework or CDR regions. In another embodiment, the antibody contains fewer than 5 amino acid changes in the framework regions and fewer than 10 changes in the CDR regions. In one preferred embodiment, the antibody contains fewer than 3 amino acid changes in the framework regions and fewer than 7 changes in the CDR regions. In a preferred embodiment, the changes in the framework regions are conservative and those in the CDR regions are somatic mutations.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 94%, preferably, at least 95%, more preferably, at least 99%, sequence(e.g., amino acid, nucleic acid, or both) identity or sequence similarity over the heavy and light chain full-length sequences, or over the heavy or the light chain, separately, with the sequences of antibody 3.1.1 , 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1, 11.2.1 (CP-675,206), 11.6.1 , 11.7.1 , 12.3.1.1 , 12.9.1.1 , ipilimumab.
• the antibody shares 100% sequence identity or sequence similarity over the heavy chain and the light chain, or with the heavy chain or the light chain, separately, of an antibody selected from antibody 3.1.1 , 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.2.1 (CP-675,206), 11.6.1 , 11.7.1, 12.3.1.1 , 12.9.1.1, ipilimumab.
• the antibody has heavy and light chain regions having the amino acid sequences of ipilimumab (previously known as MDX-010).
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 94%, more preferably, at least 95%, even more preferably, at least 99%, sequence identity or sequence similarity over the heavy and light chain full-length sequences, or over the heavy or the light chain, separately, with the sequences of germline V ⁇ A27, germline V ⁇ O12, and germline DP50 (which is an allele of the V H 3-33 gene locus). Even more preferably, the antibody shares 100% sequence identity or sequence similarity over the heavy chain sequence of germline DP50 and/or with the light chain sequence of germline A27, or germline O12.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 94%, preferably, at least 95%, more preferably, at least 99%, sequence(e.g., amino acid, nucleic acid, or both) identity or sequence similarity over the heavy and light chain variable region sequences, or over the heavy or the light chain variable region sequence, separately, with the sequences of antibody 3.1.1 , 4.1.1 , 4.8.1 , 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1 (CP-675,206), 11.6.1 , 11.7.1 , 12.3.1.1 , 12.9.1.1 , ipilimumab.
• the antibody shares 100% sequence identity or sequence similarity over the heavy chain and the light chain variable region sequences, or with the heavy chain or the light chain sequence, separately, of an antibody selected from antibody 3.1.1 , 4.1.1, 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.2.1 (CP-675,206), 11.6.1 , 11.7.1 , 12.3.1.1 , 12.9.1.1 , ipilimumab.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 94%, more preferably, at least 95%, even more preferably, at least 99%, sequence identity or sequence similarity over heavy chain variable region sequence with the heavy chain variable sequence of heavy germline DP50 (which is an allele of the V H 3-33 gene locus) or with the light chain variable sequence of germline V ⁇ A27, or germline V ⁇ 012. Even more preferably, the antibody heavy chain region sequence shares 100% sequence identity or sequence similarity with the sequence of germline DP50 or with the light chain sequence of germline A27, or germline O12.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 95%, more preferably, at least 99%, sequence identity or sequence similarity with the heavy chain, the light chain, or both, sequences from FR1 through FR4 with the FR1 through FR4 region sequences of antibody 3.1.1, 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.2.1 (CP- 675,206), 11.6.1 , 11.7.1 , 12.3.1.1 , 12.9.1.1, ipilimumab.
• the antibody shares 100% sequence identity or sequence similarity over the heavy, light, or both, sequences from FR1 through FR4 with antibody 3.1.1 , 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1 , 11.6.1 , 11.7.1 , 12.3.1.1, 12.9.1.1 , CP-675,206, and ipilimumab.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 95%, more preferably, at least 99%, and most preferably, about 100%, sequence identity or sequence similarity with the heavy chain sequences from FR1 through FR3 with the FR1 through FR3 region sequences of germline DP50.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 95%, more preferably, at least 99%, and most preferably, about 100%, sequence identity or sequence similarity with the light chain sequences from FR1 through FR4 with the FR1 through FR4 region sequences of germline V ⁇ A27, or germline V ⁇ O12.
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 95%, more preferably, at least 99%, sequence identity or sequence similarity with the heavy chain, the light chain, or both, CDR-1 , CDR-2 and CDR-3 sequences of antibody 3.1.1 , 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1, 11.2.1 (CP-675,206), 11.6.1 , 11.7.1, 12.3.1.1 , 12.9.1.1 , ipilimumab.
• the antibody shares 100% sequence identity or sequence similarity over the heavy, light, or both, CDR-1 , CDR-2 and CDR-3 sequences with antibody 3.1.1, 4.1.1, 4.8.1, 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.6.1, 11.7.1, 12.3.1.1, 12.9.1.1, CP-
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 95%, more preferably, at least 99%, and most preferably, about 100%, sequence identity or sequence similarity with the heavy chain CDR-1 and CDR-2 sequences with the
• the antibody shares at least 80%, more preferably, at least 85%, even more preferably, at least 90%, yet more preferably, at least 95%, more preferably, at least 99%, and most preferably, about 100%, sequence identity or sequence similarity with the light chain CDR-1 , CDR-2 and CDR-3 sequences with the CDR-1 , CDR-2 and CDR-3 sequences of germline V ⁇ A27, or germline V ⁇ 012.
• 01/14424 e.g., antibody ipilimumab, also known as MDX-010, Medarex, Princeton, NJ; Int.
• Patent Application No. 10/153,382 now published as U.S. Patent Application Publication No. 2003/0086930, which is incorporated by reference as if set forth in its entirety herein.
• the invention also relates to methods using antibodies comprising the amino acid sequences of the CDRs of the heavy and light chains of these antibodies, as well as those comprising changes in the CDR regions, as described in the above-cited applications and patent.
• the invention also concerns antibodies comprising the variable regions of the heavy and light chains of those antibodies.
• the antibody is selected from an antibody comprising the full length, variable region, or CDR, amino acid sequences of the heavy and light chains of antibodies 3.1.1, 4.1.1 , 4.8.1 , 4.10.2, 4.13.1 , 4.14.3, 6.1.1, 11.6.1 , 11.7.1 , 12.3.1.1 , and 12.9.1.1 , CP-675,206, and ipilimumab.
• anti-CTLA4 antibodies discussed previously herein may be preferred, the skilled artisan, based upon the disclosure provided herein, would appreciate that the invention encompasses a wide variety of anti-CTLA4 antibodies and is not limited to these particular antibodies. More particularly, while human antibodies are preferred, the invention is in no way limited to human antibodies; rather, the invention encompasses useful antibodies regardless of species origin, and includes, among others, chimeric, humanized and/or primatized antibodies. Also, although the antibodies exemplified herein were obtained using a transgenic mammal, e.g., a mouse comprising a human immune repertoire, the skilled artisan, based upon the disclosure provided herein, would understand that the present invention is not limited to an antibody produced by this or by any other particular method.
• the invention includes an anti-CTLA4 antibody produced by any method, including, but not limited to, a method known in the art (e.g., screening phage display libraries, and the like) or to be developed in the future for producing an anti-CTLA4 antibody of the invention.
• a method known in the art e.g., screening phage display libraries, and the like
• the invention includes an anti-CTLA4 antibody produced by any method, including, but not limited to, a method known in the art (e.g., screening phage display libraries, and the like) or to be developed in the future for producing an anti-CTLA4 antibody of the invention.
• a method known in the art e.g., screening phage display libraries, and the like
• the invention includes an anti-CTLA4 antibody produced by any method, including, but not limited to, a method known in the art (e.g., screening phage display libraries, and the like) or to be developed in the future for producing an anti-CTLA4 antibody of the invention.
• the present invention encompasses human antibodies produced using a transgenic non-human mammal, i.e., XenoMouseTM (Abgenix, Inc., Fremont, CA) as disclosed in the U.S. 6,682,736, to Hanson et al.
• HumanMAb-MouseTM (Medarex, Princeton, NJ), which contains human immunoglobulin gene miniloci that encodes unrearranged human heavy (mu and gamma) and kappa light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous mu and kappa chain loci (Lonberg et al. Nature 368:856-859 (1994), and U.S. Pat. No. 5,770,429).
• the invention uses human anti-CTLA4 antibodies produced using any transgenic mammal such as, but not limited to, the Kirin TC MouseTM (Kirin Beer Kabushiki Kaisha, Tokyo, Japan) as described in, e.g., Tomizuka et al., Proc Natl Acad Sci USA 97:722 (2000); Kuroiwa et al., Nature Biotechnol 18:1086 (2000); U.S. Patent Application Publication No. 2004/0120948, to Mikayama et al.; and the HuMAb-MouseTM (Medarex, Princeton, NJ) and XenoMouseTM (Abgenix, Inc., Fremont, CA), supra.
• Kirin TC MouseTM Kirin Beer Kabushiki Kaisha, Tokyo, Japan
• HuMAb-MouseTM Medarex, Princeton, NJ
• XenoMouseTM Abgenix, Inc., Fremont, CA
• the invention encompasses using an anti-CTLA4 antibody produced using any transgenic or other non-human animal.
• the antibodies employed in methods of the invention are not fully human, but “humanized”.
• murine antibodies or antibodies from other species can be “humanized” or “primatized” using techniques well known in the art. See, e.g., Winter and Harris Immunol. Today 14:43-46 (1993), Wright et al. Crit. Reviews in Immunol. 12:125-168 (1992), and US Patent No. 4,816,567, to Cabilly et al, and Mage and Lamoyi in Monoclonal Antibody Production Techniques and Applications pp. 79-97, Marcel Dekker, Inc., New York, NY (1987).
• humanized, chimeric antibodies, anti-CTLA4 antibodies derived from any species can be combined with a therapeutic agent to practice the novel methods disclosed herein.
• antibodies for use in the invention can be obtained from a transgenic non-human mammal, and hybridomas derived therefrom, but can also be expressed in cell lines other than hybridomas.
• 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), including but not limited to Chinese hamster ovary (CHO) cells, NSO, Sp2, HEK, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), and human hepatocellular carcinoma cells (e.g., Hep G2).
• ATCC American Type Culture Collection
• Non-mammalian prokaryotic and eukaryotic cells can also be employed, including bacterial, yeast, insect, and plant cells.
• Nucleic acid molecules encoding an anti-CTLA4 antibody, and expression vectors comprising these nucleic acid molecules may be used for transfection of a suitable mammalian, plant, bacterial or yeast host cell. Transformation may be by any known method for introducing polynucleotides into a host cell. Methods for introduction of heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.
• nucleic acid molecules may be introduced into mammalian cells by viral vectors.
• Methods of transforming plant cells are well known in the art, including, e.g., Agrobacterium-mediated transformation, biolistic transformation, direct injection, electroporation and viral transformation.
• Methods of transforming bacterial and yeast cells are also well known in the art.
• An expression vector may also be delivered to an expression system using DNA biolistics, wherein the plasmid is precipitated onto microscopic particles, preferably gold, and the particles are propelled into a target cell or expression system.
• DNA biolistics techniques are well-known the art and devices, e.g., a "gene gun", are commercially available for delivery of the microparticles in to a cell (e.g., Helios Gene Gun, Bio-Rad Labs., Hercules, CA) and into the skin (PMED Device, PowderMed Ltd., Oxford, UK).
• the antibody used is made in NSO cells using a glutamine synthetase system (GS-NSO).
• GS-NSO glutamine synthetase system
• the antibody is made in CHO cells using a DHFR system. Both systems are well-known in the art and are described in, among others, Barnes et al. Biotech & Bioengineering 73:261-270 (2001), and references cited therein. Site directed mutagenesis of the antibody CH2 domain to eliminate glycosylation may be preferred in order to prevent changes in either the immunogenicity, pharmacokinetic, and/or effector functions resulting from non-human glycosylation. Further, the antibody can be deglycosylated by enzymatic (see, e.g., Thotakura et al. Meth.
• an anti-CTLA4 antibody comprising an altered glycosylation pattern.
• an anti-CTLA4 antibody can be modified to comprise additional, fewer, or different glycosylates sites compared with the naturally-occurring antibody. Such modifications are described in, e.g., U.S. Patent Application Publication Nos. 2003/0207336, and 2003/0157108, and International Patent Publication Nos. WO 01/81405 and 00/24893.
• the invention comprises using an anti-CTLA4 antibody regardless of the glycoform, if any, present on the antibody.
• methods for extensively remodeling the glycoform present on a glycoprotein are well-known in the art and include, e.g., those described in International Patent Publication Nos. WO 03/031464, WO 98/58964, and WO 99/22764, and US Patent Application Publication Nos. 2004/0063911, 2004/0132640, 2004/0142856, 2004/0072290, and US Patent No. 6,602,684 to Umana et al.
• the invention encompasses using an anti-CTLA4 antibody with any art-known covalent and non-covalent modification, including, but not limited to, linking the polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in, for example, U.S. Patent Application Publication Nos. 2003/0207346 and 2004/0132640, and U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; 4,179,337.
• nonproteinaceous polymers e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes
• the invention encompasses using an anti-CTLA4 antibody, or antigen- binding portion thereof, chimeric protein comprising, e.g., a human serum albumin polypeptide, or fragment thereof.
• chimeric protein comprising, e.g., a human serum albumin polypeptide, or fragment thereof.
• the chimeric protein is produced using recombinant methods by, e.g., cloning of a chimeric nucleic acid encoding the chimeric protein, or by chemical linkage of the two peptide portions, the skilled artisan would understand once armed with the teachings provided herein that such chimeric proteins are well-known in the art and can confer desirable biological properties such as, but not limited to, increased stability and serum half-life to the antibody of the invention and such molecules are therefore included herein.
• Antibodies that are generated for use in the invention need not initially possess a particular desired isotype. Rather, the antibody as generated can possess any isotype and can be isotype switched thereafter using conventional techniques. These include direct recombinant techniques (see, e.g., U.S. Patent 4,816,397), and cell-cell fusion techniques (see e.g., U.S. Patent No. 5,916,771).
• the effector function of the antibodies of the invention may be changed by isotype switching to an IgGI , lgG2, lgG3, lgG4, IgD, IgA, IgE, or IgM for various therapeutic uses. Furthermore, dependence on complement for cell killing can be avoided through the use of bispecifics, immunotoxins, or radiolabels, for example.
• antibody 4.1.1 , 4.13.1 and 11.2.1 are lgG2 antibodies and the sequences of the variable regions of the antibodies are provided herein ( Figures 1-3), and in the applications and patents referenced and incorporated herein, it is understood that the full- length sequences of these antibodies are encompassed herein, as well as the use of any antibody comprising the sequences set forth in SEQ ID NOs: 1-36, and further comprising any constant region, regardless of isotype as more fully discussed elsewhere herein.
• any antibody comprising the full-length sequence of ipilimumab, or any portion thereof, including a sequence encoding an antigen-binding portion of ipilimumab can be used according to the methods of the invention.
• anti-CTLA4 antibody-therapeutic agent combination of the invention can comprise a wide plethora of anti-CTLA4 antibodies.
• the invention is not limited to administration of only a single antibody; rather, the invention encompasses administering at least one anti-CTLA4 antibody, e.g., one of 4.1.1 , 4.13.1, or 11.2.1 (CP-675,206), in combination with a therapeutic agent. Further, any combination of anti-CTLA4 antibodies can be combined with at least one therapeutic agent and the present invention encompasses any such combination and permutation thereof.
• the present invention relates to combinations comprising anti-CTLA4 antibody and at least one therapeutic agent, which may be further combined with additional agents and/or therapeutic modalities, e.g., chemotherapy, surgery, radiotherapy, transplantation, and the like, to treat cancer. That is, the patient may be subjected to additional chemotherapy with agents well-known, such as, but not limited to, growth factor inhibitors, biological response modifiers, alkylating agents, intercalating antibiotics, vinca alkaloids, immunomodulators, taxanes, platinum compounds, signal transduction inhibitors, selective estrogen receptor modulators (SERMs), such as, but not limited to, lasofoxifene, and angiogenesis inhibitors.
• agents well-known such as, but not limited to, growth factor inhibitors, biological response modifiers, alkylating agents, intercalating antibiotics, vinca alkaloids, immunomodulators, taxanes, platinum compounds, signal transduction inhibitors, selective estrogen receptor modulators (SERMs), such as, but not limited to, lasofoxifene, and an
• Co-administration of the antibody with an additional therapeutic agent encompasses administering a pharmaceutical composition comprising both the anti- CTLA4 antibody and one or more additional therapeutic agents, and administering two or more separate pharmaceutical compositions, one comprising the anti-CTLA4 antibody and the other(s) comprising the additional therapeutic agent(s).
• coadministration or combination (conjoint) therapy generally mean that the antibody and additional therapeutic agents are administered at the same time as one another, it also encompasses simultaneous, sequential or separate dosing of the individual components of the treatment.
• an antibody is administered intravenously and the anticancer agent is administered orally (e.g., imatinib mesylate, gemcitabine, capecitabine, temozolomide, and the like), it is understood that their combination is preferably administered as two separate pharmaceutical compositions.
• Therapeutic agents are numerous and have been described in, for instance, U.S.
• Such therapeutic agents include, but are not limited to, topoisomerase I inhibitors; other antibodies (rituximab, bevacizumab, trastuzumab, anti-IGF 1R antibody [e.g., CP-751,871], anti-CD40 antibody [e.g., CP-870,893], and the like); chemotherapeutic agents such as, but not limited to, imatinib (GLEEVEC), SU11248 (SUTENT; sunitinib), SU12662, SU14813; BAY 43-9006, AG-013736 (axitinib), immunomodulators, including toll-like receptor agonists (e.g., TLR-9 agonist; such as, but not limited to, CPG-7909, also
• the methods of the invention may be further combined with transplantation, e.g., stem cell transplantation, to provide a therapeutic benefit to a patient afflicted with breast cancer.
• transplantation may be performed according to the methods known in the art and may be allogeneic or autologous stem cell transplantation. Additionally, one skilled in the art would appreciate, based upon the disclosure provided herein, that transplantation encompasses adoptive transfer of lymphocytes, either autologous or obtained from an HLA-matched donor.
• the first dose of the antibody-AI therapy agent combination can be administered after the immune system of the mammal has recovered from transplantation, for example, in the period of from one to 12 months post transplantation.
• the first dose is administered in the period of from one to three, or one to four months post transplantation.
• Transplantation methods are described many treatises, including Appelbaum in Harrison's Principles of Internal Medicine, Chapter 14, Braunwald et al., Eds., 15 th ed., McGraw-Hill Professional (2001), which is hereby incorporated herein by reference.
• alkylating agents are a class of drugs that alkylate DNA, restricting uncoiling and replication of strands.
• a preferred alkylating agent for use in the methods of the present invention is cyclophosphamide (CYTOXAN).
• CYTOXAN cyclophosphamide
• CP- 675,206 is administered with low-dose cyclophosphamide. Without wishing to be bound by any particular theory, this is because such dose may mediate depletion of Tregs and because CTLA4 blockade appears not to affect Tregs such that these two anti-tumor mechanisms may provide a synergistic therapeutic effect.
• Folate antagonists bind to dihydrofolate reductase (DHFR) and interfere with pyrimidine (thymidine) synthesis.
• Methotrexate and pemetrexed (ALIMTA) are folate antagonists suitable for use in the methods of the present invention.
• pemetrexed also inhibits thymidylate synthase and glycinamide ribonucleotide formyl transferase, two other folate-dependant enzymes involved in thymidine synthesis.
• Pyrimidine antagonists inhibit enzymes involved in pyrimidine synthesis. As pyrimidine analogs, they also interfere with DNA production by competing with normal nucleotides for incorporation into the DNA molecule.
• Pyrimidine antagonists suitable for use in the methods of the present invention include 5-fluorouracil (5-FU); capecitabine (XELODA), a prodrug of 5'-deoxy-5-fluorouridine (5'-FDUR), which is enzymatically converted to 5-FU in vivo; and gemcitabine (GEMZAR).
• 5-fluorouracil 5-FU
• XELODA capecitabine
• 5'-FDUR a prodrug of 5'-deoxy-5-fluorouridine
• GEMZAR gemcitabine
• Anthracycline antibiotics inhibit the uncoiling of DNA by intercalation between DNA strands.
• Anthracycline antibiotics include doxorubicin hydrochloride (ADRIAMYCIN), epirubicin hydrochloride (ELLENCE, PHARMORUBICIN), daunorubicin (CERUBIDINE, DAUNOXOME), and idarubicin hydrochloride (IDAMYCIN PFS, ZAVEDOS).
• Preferred anthracyclines for use with the present invention include doxorubicin and epirubicin.
• Platinum compounds exert their anti-neoplastic effect by intercalation and intracalation between DNA strands, which inhibits uncoiling of the DNA.
• Platinum compounds useful in the methods of the present invention include cisplatin (PLATINOL), oxaliplatin (ELOXATIN), and carboplatin (PARAPLATIN).
• Taxanes promote assembly of microtubules while inhibiting their disassembly into tubulin, thereby blocking a cell's ability to break down the mitotic spindle during mitosis. They have demonstrated significant activity against many solid tumors as single agent therapy and in combination with other chemotherapy agents.
• One embodiment of the combination therapy of the present invention includes the use of one or more taxanes in combination with an IGF- 1 R antibody. Suitable taxanes for use in combination with the IGF-1 R antibody include docetaxel (TAXOTERE) and paclitaxel (TAXOL).
• Taxane-derivatives which may be active in cells resistant to doxorubicin, vinblastine, paclitaxel, docetaxel, and the like, include XRP-9981 (Sanofi Aventis), and are encompassed in the invention.
• Vinca alkaloids like taxanes, are "spindle poisons," acting on the microtubules that form the mitotic spindle. They inhibit mitosis by interfering with microtubule assembly, keeping the spindle from being formed.
• Vinca alkaloids include vindesine (ELDISINE), vinblastine sulfate (VELBAN), vincristine sulfate (ONCOVIN) and vinorelbine tartrate (NAVELBINE).
• a preferred vinca alkaloid for use in the methods of the present invention is vinorelbine.
• BMS-247550 (ixabepilone) promotes tubulin polymerization and microtubule stabilization, thereby arresting cells in the G2-M phase and inducing tumor cell apoptosis.
• This agent demonstrates activity against taxane-resistant cells.
• Analogs of rapamycin, which bind and inhibit the mammalian target of rapamycin (mTOR) are also useful and include, among others, CCI-779 (temsirolimus; Wyeth) and RAD-001 (everolimus, CERTICAN; Novartis).
• camptothecin analogs act through inhibition of topoisomerase I, an enzyme critical for DNA replication and packaging. Levels of topoisomerase I are higher in tumor cells than in normal tissue.
• a camptothecin analog useful in the methods of the present invention is irinotecan (CAMPTOSAR).
• Topoisomerase I inhibitors useful in the embodiments of the present invention include 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, and combinations thereof.
• Camptothecin derivatives are of particular interest in the combination embodiments of the invention and include camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
• topoisomerase I inhibitor is irinotecan (CAMPTOSAR)
• Topoisomerase Il inhibitors useful in the combination embodiments of the present invention include aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, and Zinecard (dexrazoxane).
• Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence), doxorubicin, daunorubicin, idarubicin and etoposide.
• Alkylating agents that may be used in the embodiments of the invention include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP- 5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, carboplatin (PARAPLATIN), eptaplatin, lobaplatin, nedaplatin, oxalip
• Antimetabolites that may be used in combination therapy with CTLA4 antibodies, optionally with one or more other agents include, but are not limited to dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists (such as 5- fluorouracil (5-FU), pemetrexed disodium (Alimta, LY231514, MTA), capecitabine (Xeloda), cytosine arabinoside, gemcitabine (Gemzar, EIi Lilly), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifl
• the anti-cancer agent is a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor such as AG-014699, ABT-472, INO-1001 , KU-0687 and GPI 18180.
• PARP-1 poly(ADP-ribose) polymerase-1
• Microtubule inhibitors that may be used in combination therapy with CTLA4 antibodies optionally with one or more other agents include, but are not limited to ABI-007, Albendazole, Batabulin, CPH-82, EPO 906 (Novartis), discodermolide (XAA-296), vinfunine and ZD-6126 (AstraZeneca).
• Antibiotics that may be used in combination therapy with CTLA4 antibodies optionally with one or more other agent including, but are not limited to, intercalating antibiotics such as actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), peplomycin, and combinations thereof.
• Plant derived anti-tumor substances also known as spindle inhibitors
• mitotic inhibitors for example vinblastine, vincristine, vindesine, vinorelbine (NAVELBINE), docetaxel
• TXOTERE Triggeraxel
• Ortataxel paclitaxel (including Taxoprexin a DHA/paciltaxel conjugate) and combinations thereof.
• Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin (ELOXATIN), Satraplatin (JM-216), and combinations thereof.
• agents include alitretinoin, l-asparaginase, AVE-8062 (Aventis), calcitriol (Vitamin D derivative), Canfosfamide (Telcyta, TLK-286), Cotara (1311 chTNT 1/b), DMXAA (Antisoma), exisulind, ibandronic acid, miltefosine, NBI-3001 (IL-4), pegaspargase, RSR13 (efaproxiral), Targretin (bexarotene), tazarotne (Vitamin A derivative), Tesmilifene (DPPE), Theratope, tretinoin, Trizaone (tirapazamine), Xcytrin (motexafin gadolinium) and Xyotax (polyglutamate paclitaxel), and combinations thereof.
• statins may be used in combination with CP-675,206.
• Statins HMG-CoA reductase inhibitors
• Atorvastatin Lipitor, Pfizer Inc.
• Pravastatin Pravastatin
• Lovastatin Mevacor, Merck Inc.
• Simvastatin Zaocor, Merck Inc.
• Fluvastatin Lescol, Novartis
• Cerivastatin Boycol, Bayer
• Rosuvastatin Crestor, AstraZeneca
• Lovostatin and Niacin Niacin
• statin is selected from the group consisting of atovorstatin and lovastatin, derivatives and combinations thereof.
• agents useful as anti-tumor agents include CADUET, Lipitor and torcetrapib.
• the above described methods are combined with a cancer vaccine described, e.g., in Rosenberg, S., Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62 (2000); Logothetis, C. ASCO Educational Book Spring: 300-302 (2000); Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., in, 1997, in Cancer: Principles and Practice of Oncology, pp. 3023-3043, Fifth Edition, DeVita, V. et al., eds. (1997), including a vaccine using autologous or allogeneic tumor cells.
• tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp 100, MAGE antigens, Trp-2.
• the tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al.
• CTLA4 inhibition can render these otherwise non-immunogenic proteins immunogenic thereby mediating an immune response to the tumor cell expressing them. That is, these proteins are normally viewed by the immune system as self antigens and are therefore tolerogenic but such tolerization can be overcome by anti-CTLA4 antibodies.
• Tumor-specific antigen can also be "neo-antigens" expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e. bcr-abl in the Philadelphia chromosome mutation for CML), or idiotype from B cell tumors.
• Other tumor vaccines can include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
• tumor-specific antigen where it is expressed by a tumor cell
• co-administration of the antigen with an anti-CTLA4 antibody can render the tumor cell subject to immune attack thus providing a therapeutic benefit.
• Another form of tumor-specific antigen which can be used in conjunction with CTLA4 antibody administration is a purified heat shock protein (HSP) isolated from the tumor tissue.
• HSP heat shock protein
• HSP-based tumor vaccines include, e.g., ONCOPHAGE (HSPPC-96), and AG-858 (HSPPC-70), both from Antigenics (Lexington, MA), among others.
• DCs are potent antigen-presenting cells that can be used to prime antigen-specific responses.
• DCs can be produced ex vivo and can be loaded with various protein and peptide antigens, as well as with tumor cell extracts (Nestle, F. et al. Nature Medicine 4:328-332 (1998)). Where the DCs are loaded with tumor cell extracts, the precise nature of the tumor antigen need not be established; rather, the DC cell processes the tumor extract and presents the antigen(s) in the context of MHC. Thus, the nature of the antigen need not be elucidated and the ability of the DCs to present it can be exploited.
• DCs can also be transduced by genetic means to express desired tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. Nature Medicine 6:332-336 (2000)). As a method of tumor vaccination, DC immunization can be effectively combined with an anti-CTLA4 antibody to mediate a more potent anti-tumor response. See also Oh et al., Cancer Res.
• an immune response to a vaccine-specific antigen may be enhanced by coadministration of anti-CTLA4 antibody.
• the present invention includes a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of an anti-CTLA4 antibody and a therapeutically effective amount of at least one therapeutic agent where the agent comprises a vaccine and/or antigen, or combination of more than one antigen, or a cell presenting an antigen and/or expressing a cytokine, e.g., GM-CSF.
• a cytokine e.g., GM-CSF.
• useful vaccines may be, without limitation, those comprised of breast cancer- associated antigens (e.g., HER-2/neu, mammaglobin, prostate and breast tumor-associated protein [TARP], MUC1 , CEA, sialyl-Tn and other carbohydrate antigens), other tumor cancer- associated antigens (e.g., p53, telomerase), anti-idiotype antibodies such as 11 D10, as well as vaccines comprising GM-CSF (see, e.g., GVAX, Cell Genesys, Inc., Lapuleucel-T [APC8024] and Sipuleucel-T [APC8015], Dendreon Corp.; and TVAX, Geron Corp.), DNA and cell-based vaccines, dendritic cell vaccines (reviewed in Banchereau & Palucka, Nature Revs.
• breast cancer- associated antigens e.g., HER-2/neu, mammaglobin, prostate and breast tumor-associated protein [TARP],
• the present invention encompasses a combination of CP-
• Tumor antigens or tumor-associated antigens include, e.g., cancer-germ cell (CG) antigens (MAGE, NY-ESO-1), mutational antigens (MUM-1 , p53, CDK-4), over-expressed self-antigens (p53, HER2/NEU), viral antigens (from Papilloma Virus, Epstein-Barr Virus), tumor proteins derived from non-primary open reading frame mRNA sequences (NY-ESO1 , LAGE1), Melan A, MART-1 , MAGE-1 , MAGE-3, BAGE, GAGE-1 , GAGE-2, tyrosinase, gplOO, gp75, HER-2/ne ⁇ /, c-erb-B2, CEA, PSA, MUC-1, CA-125, Sialyl- Tn (STn), STn-KLH (THERATOPE, Biomira Inc.
• TAAs are discussed, for example, in Palena et al., Adv. Cancer Res. 95:115-145 (2006), and other art-recognized treatises, and include use of gplOO from a non-human species, e.g., mouse gplOO, to increase or enhance an anti-tumor response.
• the TAA comprises at least one characteristic likely to be related to generating or enhancing an anti-tumor immune response.
• characteristics may include, but are not limited to, prevalence, specificity, immunogenicity, and necessity for cell viability or growth. More particularly, prevalence means the antigen is present in most patients with a certain type of cancer. In another embodiment, the more types of cancer cells that express the antigen compared with expression of the antigen by normal cells the more desirable the prevalence would be.
• the TAA is specific for the cancer cells in that the expression of the TAA is significantly greater on a cancer cell compared with the level of expression of the TAA on an otherwise identical but non-cancer cell, more preferably, the TAA is not detectably expressed on a normal cell but is expressed on most, if not all, cancer cells in a patient. Most preferably, the TAA is unique to a tumor cell and is not expressed in a normal cell. In yet another embodiment, the TAA is immunogenic, e.g., it induces a detectable immune response to a tumor cell. More specifically, the higher the magnitude of the response, the more preferred the TAA. Even more preferably, the TAA induces, increases and/or prolongs a cellular immune response.
• the TAA is vital to cell growth or survival. That is, the TAA is needed by a tumor cell to survive, grow and/or proliferate. Even more preferably, the TAA is vital to a tumor cell such that affecting or inhibiting a biological activity of the TAA prevents or inhibits cell survival or proliferation. Even more preferably, the TAA is vital such that inhibiting or reducing a biological activity of the antigen inhibits development or selection of a tumor cell variant not expressing the antigen or a variant cell expressing a mutant antigen not affected by the anti-tumor immune response to the original TAA. That is, inducing an immune response to the antigen prevents or inhibits cell survival such that a variant antigen that avoids the immune response is not selected.
• CP-675,206 is administered to a patient (e.g., a melanoma patient) previously vaccinated using a tumor vaccine (e.g., a MART-1 antigen), thereby inducing, enhancing and/or prolonging an immune response to the vaccine, thereby providing a therapeutic benefit to the patient.
• a tumor vaccine e.g., a MART-1 antigen
• CP-675,206 can be administered with at least one additional therapeutic agent, such as, but not limited to, a chemotherapeutic agent, an immunomodulatory agent (a TLR-9 agonist), an immune enhancing antibody (e.g., an agonist anti-CD40 antibody), among many additional agents.
• a vaccines is be administered prior to, or subsequent to, administration of the antibody-therapeutic agent combination, and when chemotherapy is part of the regimen, a vaccine may be administered prior to chemotherapy.
• the antibody-therapeutic agent combination of the invention may also be administered prior to chemotherapy.
• the treatment can be combined with stem cell transplant. That is, the antibody-chemotherapeutic agent combination can be administered before or after stem cell transplant.
• a vaccine may also be administered before or after stem cell transplantation and, in certain embodiments, concomitantly with the antibody.
• Stem cell transplantation may be performed according to the methods known in the art. Some such methods are described in Appelbaum in Harrison's Principles of Internal Medicine, Chapter 14, Braunwald et al., Eds., 15 th ed., McGraw-Hill Professional (2001), which is hereby incorporated herein by reference.
• the methods of the present invention relate to the treatment of cancer in a mammal who has undergone stem cell transplantation, which methods comprise administering to the mammal an amount of a human anti-CTLA4 antibody in combination with a therapeutic agent, which combination is effective in treating the cancer in further combination with stem cell transplantation.
• the first dose of the antibody- therapeutic agent combination can be administered after the immune system of the mammal has recovered from transplantation, for example, in the period of from one to 12 months post transplantation. In certain embodiments, the first dose is administered in the period of from one to three, or one to four months post transplantation.
• the patient may undergo stem cell transplantation and preparatory treatment(s).
• an anti-CTLA4 antibody is combined with a standard cancer treatment, such as, inter alia, chemotherapeutic regimes, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. Cancer Research 58: 5301-5304 (1998)). This is because combined use of an anti-CTLA4 antibody and chemotherapy can mediate cell death that is a consequence of the cytotoxic action of most chemotherapeutic compounds. Such cell death likely results in increased levels of tumor-specific antigen in the antigen presentation pathway, and the anti-CTLA4 antibody mediates an increased immune response thereto.
• combination therapies that can result in synergy with anti-CTLA4 enhancement of the immune response through cell death release of tumor antigens are radiation, surgery, and hormone deprivation, among many others. Each of these protocols, and others described elsewhere herein, creates a source of tumor antigen in the host.
• angiogenesis and signal inhibitors can also be combined with an anti-CTLA4 antibody to increase an immune response to a tumor cell since inhibition of angiogenesis or signal transduction can lead to tumor cell death which may feed tumor antigen into host antigen presentation pathways. Therefore, the combination therapies disclosed herein can provide an increased source of tumor-specific antigens thereby providing an increased immune response to the tumor which, in turn, provides a therapeutic benefit to the patient.
• the present invention encompasses a combination of an anti- CTLA4 antibody and at least one signal transduction inhibitor, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses (e.g., EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors); VEGF (vascular endothelial growth factor) inhibitors (e.g., VEGF receptors and molecules that can inhibit VEGF); and erbB2 receptor (HER2) inhibitors (e.g., small molecules or antibodies that bind to the erbB2 receptor, where exemplary antibodies include trastuzumab and pertuzumab, which is a HER dimerization inhibitor (HDI)).
• EGFR epidermal growth factor receptor
• VEGF vascular endothelial growth factor
• HER2 receptor e.g., small molecules or antibodies that bind to the erbB2 receptor, where exemplary antibodies include trastuzumab and pertuzumab, which is a HER dimerization
• EGFR inhibitors are described in, for example in International Patent Publication Nos. WO 95/19970, WO 98/14451, WO 98/02434, and U.S. Patent No. 5,747,498, and such substances can be used in the present invention as described herein.
• EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225, anti-EGFR 22Mab (ImClone Systems Inc., New York, NY), and ABX-EGF (Abgenix Inc., remont, CA), the compounds ZD- 1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarexjn ⁇ , Annandale, NJ), and OLX-103 (Merck & Co., Whitehouse Station, NJ), TP-38 (IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFR immunoliposomes (Hermes Biosciences Inc.), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc., Hopkinton, MA). These and other EGFR- inhibiting agents can be used in the present invention in combination with anti-CTLA4 antibody to treat various cancers.
• EGFR epidermal growth factor receptor
• TK tyrosine kinase
• EGFR- TK inhibitors may selectively target one of the members of the EGFR family (EGFR (also known as HER1 or ErbB-1), HER2/neu (also known as ErbB-2), HER3 (also known as ErbB- 3), or HER4 (also known as ErbB-4)), or may target two or more of them.
• EGFR also known as HER1 or ErbB-1
• HER2/neu also known as ErbB-2
• HER3 also known as ErbB- 3
• HER4 also known as ErbB-4
• EGFR-TK inhibitors suitable for use in the present invention include gefitinib (IRESSA), erlotinib (TARCEVA), Cl- 1033 (Pfizer), GW2016 (GlaxoSmithKline), EKB-569 (Wyeth), PKI-166 (Novartis), CP- 724,714 (Pfizer), CI-1033 (canertinib, Pfizer Inc), and BIBX-1382 (Boeringer-lngelheim). Additional EGFR-TK inhibitors are described in U.S. Patent No. 6,890,924. VEGF inhibitors, for example SU-5416, SU-6668, SU-11248, SlM 2662, SU-14813
• VEGF inhibitors are described, for example, in International Patent Application No. PCT/IB99/00797 (filed May 3, 1999), International Patent Publication Nos. WO 95/21613; WO 97/22596 (published June 26, 1997); WO 97/32856 (published Sept. 12, 1997); WO 98/02437 and WO 98/02438 (both published Jan. 22, 1998); WO 98/50356; WO 98/54093 (published Dec.
• VEGF inhibitors useful in the present invention are vandetanib (Zactima), sorafenib (Bayer/Onyx), AEE788 (Novartis), AZD-2171 , VEGF Trap (Regeneron/Aventis), vatalinib (also known as PTK-787, ZK-222584; Novartis/Schering AG as described in U.S. Pat. No.
• MACUGEN pegaptanib octasodium, NX-1838, EYE-001 ; Pfizer Inc/Gilead/Eyetech), IM862 (Cytran Inc., Kirkland, WA); neovastat (Aeterna), IMC-1C11 ImClone antibody, bevacizumab (AVASTIN, Genentech, Inc., San Francisco, CA); cetuximab (ERBITUX, ImCIone); and ANGIOZYME, a synthetic ribozyme that cleaves mRNA producing VEGF1 from Ribozyme (Boulder, CO) and Chiron (Emeryville, CA).
• ErbB2 receptor inhibitors such as GW-282974, GW-572016 (lapatinib) (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc., Woodlands, TX), mapatumumab (HGS-ETR1, Human Genome Sciences, Inc.) an agonist of TRAIL Receptor 1), trastuzumab (HERCEPTIN; Genentech, Inc., San Francisco, CA), pertuzumab (OMNITARG; 2C4; Genentech, a HER2 dimerization inhibitor HDI)); TAK-165 (Takeda), GW-572016 (lapatinib, GlaxoSmithKline), pelitinib (EKB-569 Wyeth), BMS-599626, PKI-166 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), Osidem (IDM-1), APC8024 (HER2 Vaccine, Den
• erbB2 receptor inhibitors are described in, for example, International Patent Publication Nos. WO 95/19970 (published July 27, 1995); WO 97/13760 (published April 17, 1997); WO 98/02434 (published January 22, 1998); WO 98/02437 (published January 22, 1998); WO 99/35132 (published July 15, 1999); WO 99/35146 (published July 15, 1999); U.S. Patent Nos. 5,587,458, and 5,877,305.
• ErbB2 receptor inhibitors useful in the present invention are also described in EP1029853 (published August 23, 2000) and in International Patent Publication No. WO 00/44728, (published August 3, 2000). ErbB2 receptor inhibitors useful in the present invention are also described in United States Patent Nos.
• WO 96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21 , 1997), WO 98/02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose.
• RAF kinase is an enzyme in the RAS pathway and mutations in the RAS gene are associated with approximately 20% of all human cancers, including 90% of pancreatic cancer, 50% of colon cancer and about 30% of non-small cell lung cancer (NSCLC), and BRAF, a specific RAF kinase, has been demonstrated to be mutated in about two-thirds of melanomas and some colorectal cancer (CRC) and other solid tumors.
• VEGFR and PDGFR- ⁇ play key roles in angiogenesis such that their inhibition decreases angiogenesis.
• the present invention encompasses administering a combination comprising an anti-CTLA4 antibody and BAY 43- 9006 to treat cancer.
• PDGFR inhibitors include but not limited to those disclosed in Int. Pat. Pub. No. WO
• Preferred PDGFR inhibitors include Pfizer's CP-673,451 and CP-868,596 and their pharmaceutically acceptable salts.
• TIE-2 inhibitors include GlaxoSmithKline's benzimidazoles and pyridines including
• TIE-2 inhibitors include Regeneron's biologicals such as those described in Int. Pat. Pub. No. WO 09/611269 published April 18, 1996, Amgen's AMG-386, and Abbott's pyrrolopyrimidines such as A-422885 and BSF-466895 described in Int. Pat. Pub. Nos. WO 09/955335, WO 09/917770, WO 00/075139, WO 00/027822, WO 00/017203 and WO 00/017202.
• an angiogenesis inhibitor includes, but is not limited to, bevacizumab (AVASTIN) which is a humanized antibody to VEGF.
• Bevacizumab can be used in combination with 5FU, and is indicated as a first-line treatment of patients with metastatic carcinoma of the colon or rectum.
• Agents that directly target angiogenic factors or their receptors offer the prospect for greater activity in receptor- competent hematologic malignancies by interrupting autocrine receptor signaling.
• Bevacizumab produces sustained neutralization of circulating VEGF and may be useful for treatment of myelodysplastic syndrome (MDS), lymphoma, acute myeloid leukemia (AML), and solid tumors.
• MDS myelodysplastic syndrome
• AML acute myeloid leukemia
• solid tumors solid tumors.
• an anti-CTLA4 antibody and bevacizumab combination therapy in further combination with 5FU and additional chemotherapeutic agents, for treatment of CRC, and other malignancies, is encompassed by the present invention.
• the anti-angiogenesis agent is a protein kinase C Ii such as enzastaurin, midostaurin, perifosine, staurosporine derivative (such as RO 318425, RO317549, RO318830 or RO 318220 (Roche)), teprenone (Selbex) and UCN-01 (Kyowa Hakko).
• a protein kinase C Ii such as enzastaurin, midostaurin, perifosine, staurosporine derivative (such as RO 318425, RO317549, RO318830 or RO 318220 (Roche)), teprenone (Selbex) and UCN-01 (Kyowa Hakko).
• the receptor tyrosine kinase inhibitors represent a class of synthetic, small molecule inhibitors of angiogenic receptor signaling.
• the first receptor antagonist to enter clinical testing in hematologic malignancies is SU5416 (Sugen), which impairs ligand-induced autophosphorylation of the VEGFR-1 and VEGFR-2 receptors and c-Kit.
• SU5416 inhibits VEGF-induced clonogenic response in leukemia cell lines and promotes apoptosis in myeloblasts from AML patients.
• RTKIs including SU11248 (sunitinib), SU12662, SU14813, (Pfizer Inc.), vatalanib (also known as PTK787/ZK222584; Novartis), and AG- 013736 (Pfizer), can be used in combination with an anti-CTLA4 antibody to treat AML and other receptor-competent hematologic malignancies.
• CP-675,206 may be combined with sunitinib (SU-11248), among other RTKIs.
• the present invention encompasses a combination of an anti-CTLA4 antibody and at least one antiangiogenic and/or signal transduction inhibitor, including, e.g., SU-11248, SU-12662, SU-14813, AG-013736, as well as other angiogenesis and signal transduction inhibitors that are well-known in the art or developed in the future.
• at least one antiangiogenic and/or signal transduction inhibitor including, e.g., SU-11248, SU-12662, SU-14813, AG-013736, as well as other angiogenesis and signal transduction inhibitors that are well-known in the art or developed in the future.
• the combination therapy methods of the invention can be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to other agents capable of enhancing antitumor immune responses, such as additional, different, CTLA4 antibodies, and other agents also capable of blocking CTLA4; and antiproliferative agents such as farnesyl protein transferase inhibitors, and ⁇ v ⁇ 3 inhibitors, such as the ⁇ v ⁇ 3 antibody VITAXIN, ⁇ v ⁇ 5 inhibitors, p53 inhibitors, and the like.
• agents capable of enhancing antitumor immune responses such as additional, different, CTLA4 antibodies, and other agents also capable of blocking CTLA4
• antiproliferative agents such as farnesyl protein transferase inhibitors, and ⁇ v ⁇ 3 inhibitors, such as the ⁇ v ⁇ 3 antibody VITAXIN, ⁇ v ⁇ 5 inhibitors, p53 inhibitors, and the like.
• the immunomodulatory agent can be selected for example from the group consisting of a dendritic cell activator such as CD40 ligand and anti-CD40 agonist antibodies, as well as enhancers of antigen presentation, enhancers of T-cell tropism, inhibitors of tumor-related immunosuppressive factors, such as TGF- ⁇ (transforming growth factor beta), and IL-10.
• a dendritic cell activator such as CD40 ligand and anti-CD40 agonist antibodies
• enhancers of antigen presentation such as CD40 ligand and anti-CD40 agonist antibodies
• enhancers of T-cell tropism such as enhancers of T-cell tropism
• inhibitors of tumor-related immunosuppressive factors such as TGF- ⁇ (transforming growth factor beta), and IL-10.
• TGF- ⁇ transforming growth factor beta
• US2003/0211100 including, but not limited to, an antibody having the heavy and light chain amino acid sequence of antibody 3.1.1 , 3.1.1.H-A78T, 3.1.1 H-A78T-V88 A- V97A, 3.1.1 L-L4M-L83V, 3.1.1 H-A78T-V88A-V97A/3.1.1 L-L4M-L83V, 7.1.2, 10.8.3, 15.1.1 , 21.2.1 , 21.4.1 , 22.1.1 , 22.1.1 H-C109A, 23.5.1 , 23.25.1 , 23.28.1 , 23.28.1 H-D16E, 23.29.1 , and 24.2.1.
• the present treatment regimens may also be combined with antibodies or other ligands that inhibit tumor growth by binding to IGF-1 R (insulin-like growth factor 1 receptor).
• IGF-1 R insulin-like growth factor 1 receptor
• Specific anti-IGF-1 R antibodies that can be used in the present invention include those described in International Patent Application No. PCT/US01/51113, filed 12/20/01 , and published as International Patent Publication No. WO02/053596, International Patent Application No. PCT/IB2004/002555, filed August 3, 2004, and published as International Patent Publication No. WO 2005/016967.
• Preferred anti-IGFR-1 R antibodies encompass an antibody having the heavy and light chain amino acid sequence of, e.g., antibody 2.12.1 , 2.13.2, 2.14.3, 3.1.1 , 4.9.2 and 4.17.3.
• Ligands that inhibit signaling via the IGF-1R also encompass small molecules, and other ligands including, inter alia, somavert (PEGVISOMANT), which is a growth hormone analog that inhibits IGF-1 signaling.
• PEGVISOMANT is conjugated with polyethylene glycol and can be used, among other things, to treat acromegaly.
• PEGVISOMANT can be co- administered with anti-CTLA4 antibody to treat cancer in that the combination can inhibit tumor growth.
• PEGVISOMANT similarly with anti-IGF-1 R antibodies, can be used in combination with an anti-CTLA4 antibody to treat cancer as disclosed herein.
• Additional exemplary therapeutic and/or prophylactic antibodies include, but are not limited to, SYNAGIS (Medlmmune, MD) which is a humanized anti-respiratory syncytial virus (RSV) monoclonal antibody; REMICADE (infliximab) (Centocor, PA) which is a chimeric anti- TNF ⁇ monoclonal antibody; REOPRO (abciximab) (Centocor) which is an anti-glycoprotein llb/llla receptor; ZENAPAX (daclizumab) (Roche Pharmaceuticals, Switzerland) which is a humanized anti-CD25 monoclonal antibody; AVASTIN (bevacizumab); matuzumab (Merck AG), nimotuzumab, panitumumab, EGFR inhibitor antibody (Amgen/Abgenix); ERBITUX (cetuximab).
• SYNAGIS Medlmmune, MD
• RSV humanized anti-res
• a humanized anti-CD18 F(ab') 2 (Genentech); CDP860 which is a humanized anti CD18 F(ab') 2 (Celltech, UK); PRO542 which is an anti-HIV gp120 antibody fused with CD4 (Progenics/Genzyme Transgenics); OSTAVIR which is a human anti Hepatitis B virus antibody (Protein Design Lab/Novartis); PROTOVIR which is a humanized anti-CMV IgGI antibody (Protein Design Lab/Novartis); MAK-195 (SEGARD) which is a murine-anti-TNF- ⁇ F(ab') 2 (Knoll Pharma/BASF); IC14 which is an anti-CD14 antibody (ICOS Pharm); a humanized anti-VEGF IgGI antibody (Genentech); OVAREX which is a murine anti-CA 125 antibody (Altarex); PANOREX which is a murine anti-17-IA cell surface antigen
• the agent used in conjunction with CP-675,206 is a hepatocyte growth factor receptor (HGFR or c-MET) antagonist.
• CP-675,206 or ipilimumab is administered with an antibody to MAdCAM to treat cancer.
• the nucleotide sequence encoding an antibody or other immunoreactive reagent may be obtained from any information available to those of skill in the art (i.e., from Genbank, the literature, or by routine cloning).
• a nucleic acid encoding the immunoglobulin or other immunoreactive reagent may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody) by any method, including, e.g., PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g. a cDNA clone from a cDNA library that encodes
• the anti-CTLA4 antibody may also be administered with a cytokine such as, e.g., interleukin (e.g., IL-1 ⁇ , IL- 1 ⁇ , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, IL-18), interferon (e.g., IFN ⁇ , IFN ⁇ , IFN ⁇ ), tumor necrosis factor (e.g., TNF ⁇ , TNF ⁇ ), G-CSF, GM-CSF, TGF- ⁇ , SLC, endothelial monocyte activating protein-2 (EMAP2), MIP-3 ⁇ , MIP-3 ⁇ , or an MHC gene, such as HLA-B7.
• a cytokine such as, e.g., interleukin (e.g., IL-1 ⁇ , IL- 1 ⁇ , IL-2, IL-3, IL-4, IL-5,
• CTLA4 blockade is co-administered with IL-15 or an agonist thereof, to increase, induce or prolong an immune response.
• IL-15 or an agonist thereof
• coadministration of a CTLA4 antagonist in combination with IL-15, or an agonist of IL-15/IL-15R may enhance a therapeutic anti-tumor response, and may provide a greater immune response than either agent alone, and more preferably, may provide a synergistic effect greater than the additive effect of each agent combined.
• combination therapy comprising an anti-CTLA4 antibody and an agonist of the IL-
• 15/IL-15R signaling pathway e.g., IL-15, an agonist anti-IL15 antibody, an agonist anti-IL-15R antibody, among others
• IL-15 an agonist anti-IL15 antibody
• agonist anti-IL-15R antibody an agonist anti-IL-15R antibody, among others
• Additional exemplary cytokines include other members of the TNF family, including, but not limited to, TNF- ⁇ -related apoptosis-inducing ligand (TRAIL), TNF- ⁇ -related activation- induced cytokine (TRANCE), TNF- ⁇ -related weak inducer of apoptosis (TWEAK), CD40 ligand (CD40L), LT- ⁇ , LT- ⁇ , OX40L, FasL, CD27L, CD30L, 4-1 BBL, APRIL, LIGHT, TL1 , TNFSF16, TNFSF17, and AITR-L, or a functional portion thereof. See, e.g., Kwon et al., Curr. Opin. Immunol. 11 :340-345 (1999) for a general review of the TNF family.
• interferons and numerous other immune enhancing agents that may be used in combination therapy with CP-675,206 include, but are not limited to interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune), or interferon gamma-n1 , PEG lntron A, and combinations thereof.
• agents include interleukin 2 agonists (such as aldesleukin, BAY-50-4798, Ceplene (histamine dihydrochloride), EMD-273063, MVA-HPV-IL2, HVA-Muc-1-IL2, interleukin 2, teceleukin and Virulizin), Ampligen, Canvaxin, CeaVac (CEA), denileukin, filgrastim, Gastrimmune (G17DT), gemtuzumab ozogamicin, Glutoxim (BAM-002), GMK vaccine (Progenies), Hsp 90 inhibitors (such as HspE7 from Stressgen, AG-858, KOS-953, MVJ-1-1 and STA-4783), imiquimod, krestin (polysaccharide K), lentinan, Melacine (Corixa), MelVax (mitumomab), molgramostim, Oncophage (HSPPC-96), OncoVAX (including Onco
• the present invention includes coadministration of an anti-CTLA4 antibody, or combination of such antibodies, with at least one T cell costimulatory molecule (also referred to herein as a "costim"), including, but not limited to, CD4, CD25, and the like.
• Costimulatory molecules further include, e.g., PD-1, B7-H3, OX40, ICOS, CD30, HLA-DR, MHCII, and LFA, or agonist antibodies thereto.
• costims are well-known in the art and have been well characterized as described in, e.g., Schwartz et al., Nature 410:604-608 (2001); Schwartz et al., Nature Immunol. 3:427-434 (2002); and Zhang et al., Immunity 20:337-347 (2004).
• CP-675,206 or ipilimumab is administered with an antibody to human 4-1BB to treat cancer.
• Suitable anti-4-1 BB antibodies are described in, e.g., Int. Appl. No. PCT/US2004/033587 (published April 21 , 2005, as WO 2005/035584).
• One such antibody is BMS66513.
• CP-675,206 or ipilimumab is administered with an antibody to human mucosal addressin cell adhesion molecule (MAdCAM) to treat cancer.
• MAdCAM mucosal addressin cell adhesion molecule
• Suitable anti-MAdCAM antibodies are described in, e.g., Int. Appl. No.
• the anti- MAdCAM antibody is an antibody comprising a heavy and light chain variable region amino acid sequence of antibody 1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1 , 6.73.2, 6.77.1 , 7.16.6, 7.20.5, 7.26.4, and 9.8.2.
• anti-CTLA4 In addition to combination of anti-CTLA4 and immunostimulatory compounds to increase an anti-tumor immune response, it would be understood that certain immunosuppressive molecules may inhibit or decrease an anti-tumor response. Accordingly, in another embodiment of the invention, anti-CTLA antibody is administered in combination with an inhibitor of an immunosuppressive molecule.
• immunosuppressive molecules include, but are not limited to, IDO, TGF- ⁇ , PD-1, among others.
• anti-angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix- metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with the antibody in the method of the invention.
• MMP-2 matrix-metalloproteinase 2
• MMP-9 matrix- metalloproteinase 9
• COX-II cyclooxygenase II
• COX-II inhibitors examples include CELEBREX (celecoxib), parecoxib, deracoxib, ABT-963, COX-189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), Vioxx (rofecoxib), SD- 8381 , 4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H-pyrrole, 2-(4-ethoxyphenyl)- 4-methyl-1-(4-sulfamoylphenyl)-1 H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC- 58125 and Arcoxia (etoricoxib).
• COX-II inhibitors are disclosed in U.S. Patent Application Nos. 10/801 ,446 and 10/801,429, the contents of which are incorporated in their entirety for all purposes.
• the agent is celecoxib as disclosed in U.S. Patent No. 5,466,823, the contents of which are incorporated by reference in its entirety for all purposes.
• the agent is deracoxib as disclosed in U.S. Patent No. 5,521 ,207, the contents of which are incorporated by reference in its entirety for all purposes.
• NSAIDs non-steroidal anti-inflammatory drugs
• Such agents include, but are not limited to, Aposyn (exisulind), Salsalate (Amigesic), Diflunisal (Dolobid), lbuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), lndomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxaprozin (Daypro) and combinations thereof.
• Preferred nonselective cyclooxygenase inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof.
• Other anti-angiogenic compounds include acitretin, angiostatin, aplidine, cilengtide,
• COL-3 combretastatin A-4, endostatin, fenretinide, halofuginone, Panzem (2- methoxyestradiol), PF03446962 (ALK-1 inhibitor), rebimastat, removab, Revlimid, squalamine, thalidomide, ukrain, Vitaxin (alpha-v/beta-3 integrin), and zoledronic acid.
• MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP- 8, MMP-10, MMP-11 , MMP-12, and MMP-13).
• MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP- 8, MMP-10, MMP-11 , MMP-12, and MMP-13 matrix-metalloproteinases
• MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, ABT-510 (Abbott), ABT 518 (Abbott), Apratastat (Amgen), AZD 8955 (AstraZeneca), Neovostat (AE-941), COL 3 (CollaGenex Pharmaceuticals), doxycycline hyclate, MPC 2130 (Myriad) and PCK 3145 (Procyon), and the compounds recited in the following list: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]- propionic acid;
• the agent is a signal transduction inhibitor.
• Such inhibitors include small molecules, antibodies, and antisense molecules, and encompass tyrosine kinase inhibitors, serine/threonine kinase inhibitors. More specifically, signal transduction inhibitors include farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-
• the signal transduction inhibitor is a famesyl protein transferase inhibitor.
• Famesyl protein transferase inhibitors include the compounds disclosed and claimed in United States Patent 6,194,438, issued February 27, 2002; United States Patent 6,258,824, issued July 10, 2001 ; United States Patent 6,586,447, issued July 1 , 2003; United States Patent 6,071 ,935, issued June 6, 2000; and United States Patent 6,150,377, issued November 21 , 2000.
• Other famesyl protein transferase inhibitors include AZD-3409 (AstraZeneca), BMS-214662 (Bristol-Myers Squibb), Lonafarnib (Sarasar) and RPR-115135 (Sanofi-Aventis).
• the signal transduction inhibitor is a GARF inhibitor.
• GARF inhibitors include Pfizer's AG- 2037 (pelitrexol) and its pharmaceutically acceptable salts.
• GARF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 5,608,082, which is incorporated in its entirety for all purposes.
• the signal transduction inhibitor is a MEK inhibitor.
• MEK inhibitors include Pfizer's MEK1/2 inhibitor PD325901 , Array Biopharm's MEK inhibitor ARRY- 142886, and combinations thereof.
• the anti-cancer signal transduction inhibitor is an mTOR inhibitor.
• mTOR inhibitors include everolimus (RAD001 , Novartis), zotarolimus, temsirolimus (CCI-779, Wyeth), AP 23573 (Ariad), AP23675, Ap23841 , TAFA 93, rapamycin (sirolimus), and combinations thereof.
• the anti-cancer signal transduction inhibitor is an Aurora 2 inhibitor such as VX-680 and derivatives thereof (Vertex), R 763 and derivatives thereof (Rigel), and ZM 447439 and AZD 1152 (AstraZeneca), or a Checkpoint kinase 1/2 inhibitors such as XL844 (Exilixis).
• Aurora 2 inhibitor such as VX-680 and derivatives thereof (Vertex), R 763 and derivatives thereof (Rigel), and ZM 447439 and AZD 1152 (AstraZeneca), or a Checkpoint kinase 1/2 inhibitors such as XL844 (Exilixis).
• the anti-cancer signal transduction inhibitor is an Akt inhibitor (Protein Kinase B) such as API-2, perifosine and RX-0201.
• Akt inhibitor Protein Kinase B
• targeted anti-cancer agents include the raf inhibitors sorafenib (BAY- 43-9006, Bayer/Onyx), GV-1002, ISIS-2503, LE-AON and GI-4000, BMS 184476, CCI 779, DTIC, ISIS 2503, ONYX 015, and flavopyridol.
• the invention also relates to methods comprising CP-675,206 and cell cycle inhibitors such as the CDK2 inhibitors ABT-751 (Abbott), AZD-5438 (AstraZeneca), alvocidib (flavopiridol, Aventis), BMS-387,032 (SNS 032 Bristol Myers), EM-1421 (Erimos), indisulam (Esai), seliciclib (Cyclacel), BIO 112 (One Bio), UCN-01 (Kyowa Hakko), and AT7519 (Astex Therapeutics) and Pfizer's multitargeted CDK inhibitors PD0332991 and AG24322.
• cell cycle inhibitors such as the CDK2 inhibitors ABT-751 (Abbott), AZD-5438 (AstraZeneca), alvocidib (flavopiridol, Aventis), BMS-387,032 (SNS 032 Bristol Myers), EM-1421 (Erimos), indisul
• the invention also relates to the use of CP-675,206 together with telomerase inhibitors such as transgenic B lymphocyte immunotherapy (Cosmo Bioscience), GRN 163L (Geron), GV1001 (Pharmexa), RO 254020 (and derivatives thereof), and diazaphilonic acid.
• telomerase inhibitors such as transgenic B lymphocyte immunotherapy (Cosmo Bioscience), GRN 163L (Geron), GV1001 (Pharmexa), RO 254020 (and derivatives thereof), and diazaphilonic acid.
• the invention also relates to the use of CP-675,206 with hormonal, anti-hormonal, anti-androgenal therapeutic agents such as anti-estrogens including, but not limited to toremifene, raloxifene, anti-androgens such as finasteride, mifepristone, ABARELIX (Praecis),
• hormonal, anti-hormonal, anti-androgenal therapeutic agents such as anti-estrogens including, but not limited to toremifene, raloxifene, anti-androgens such as finasteride, mifepristone, ABARELIX (Praecis)
• TRELSTAR ATAMESTANE (Biomed-777), ATRASENTAN (Xinlay), Bosentan, doxercalciferol, and combinations thereof.
• the invention also contemplates the use of CP-675,206 together with gene silencing agents or gene activating agents such as histone deacetylase (HDAC) inhibitors such as suberolanilide hydroxamic acid (SAHA, Merck Inc/Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101.
• HDAC histone deacetylase
• the invention also contemplates the use of CP-675,206 with gene therapeutic agents such as ADVEXIN (ING 201), TNFerade (GeneVec, a compound which express TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine).
• ADVEXIN ING 201
• TNFerade GeneVec, a compound which express TNFalpha in response to radiotherapy
• RB94 Breast Cancer College of Medicine
• the invention also contemplates CP-675,206 together with ribonucleases such as Onconase (ranpimase).
• the invention also contemplates CP-675,206 with antisense oligonucleotides such as bcl-2 antisense inhibitor Genasense (Oblimersen, Genta).
• antisense oligonucleotides such as bcl-2 antisense inhibitor Genasense (Oblimersen, Genta).
• Genasense Opblimersen, Genta
• proteosomics such as PS-
• the invention also contemplates CP-675,206 together with anti-vascular agents such as Combretastatin A4P (Oxigene).
• the invention also contemplates combination of CP-675,206 with traditional cytotoxic agents including DNA binding agents, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, topoisomerase inhibitors and microtubulin inhibitors.
• an anti-CTLA4 antibody is administered to a patient receiving a chemotherapeutic agent for treatment of cancer.
• chemotherapeutic agents include, but are not limited to: methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposides, camptothecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, and docetaxel, doxorubicin, epirubicin, 5-fluorouracil, taxanes
• suitable chemotherapeutics include, but are not limited to, alkylating agents: nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil); nitrosoureas (e.g., carmustine (BCNU), lomustine (CCNU)); alkylsulphonates (e.g., busulfan, treosulfan); triazenes (e.g., dacarbazine); Platinum containing compounds (e.g., cisplatin, carboplatin, aroplatin, oxaliplatin); Plant Alkaloids: Vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinorelbine); Taxoids (e.g., paclitaxel, docetaxel; DNA Topoisomerase Inhibitors: epipodophyllins (e.g., etoposide, teniposide
• costimulatory molecules e.g., CD4, CD25, PD-1 , B7-H3, 4-1BB, OX40, ICOS, CD30, HLA-DR, MHCII, and LFA, and agonist antibodies thereto; among many other agents known in the art.
• Additional anti-cancer agents that may be used in the methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amifostine trihydrate; aminoglutethimide; amsacrine; anastrozole; anthramycin; arsenic trioxide; asparaginase; asperlin; azacitidine; azetepa; azotomycin; Bacillus Calmette-Guerin; batimastat; benzodepa; bevacizumab; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; bortezomib; brequinar sodium; bropirimine; busulfan; cactin
• anti-cancer drugs that can be used include, but are not limited to: 20-epi-1 ,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-
• ICOS castanospermine
• cecropin B cetrorelix
• chlorlns chloroquinoxaline sulfonamide
• cicaprost cis-porphyrin
• cladribine clomifene analogues
• clotrimazole collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverap
• a combination comprising an anti-CTLA4 antibody and a second therapeutic agent is administered to a subject receiving radiation therapy for treatment of cancer.
• the radiation can be gamma rays or X-rays.
• the methods encompass treatment of cancer comprising radiation therapy, such as external- beam radiation therapy, interstitial implantation of radioisotopes (1-125, palladium, iridium), radioisotopes such as strontium-89, thoracic radiation therapy, intraperitoneal P-32 radiation therapy, and/or total abdominal and pelvic radiation therapy.
• the radiation treatment is administered as external beam radiation or teletherapy wherein the radiation is directed from a remote source.
• the radiation treatment is administered as internal therapy or brachytherapy wherein a radiaoactive source is placed inside the body close to cancer cells or a tumor mass.
• Radiation therapy can be administered in accordance to well-known radiotherapy methods for treatment of cancer.
• the dose and regimen for radiotherapy can be readily determined by one skilled in the art and is based on the stage of the disease, and other factors well-known in the art.
• Hellman In: Principles of Cancer Management: Radiation Therapy, Chapter 16, DeVita et al., eds., 6th edition, 2001 , J. B. Lippencott Company, Philadelphia.
• Co-administration of the antibody with at least one therapeutic agent encompasses administering a pharmaceutical composition comprising both the anti- CTLA4 antibody and one or more therapeutic agent(s), and administering two or more separate pharmaceutical compositions, one comprising the anti-CTLA4 antibody and the other(s) comprising the therapeutic agent(s).
• co-administration or combination (conjoint) therapy generally mean that the antibody and additional therapeutic agents are administered at the same time as one another, it also encompasses simultaneous, sequential or separate dosing of the individual components of the treatment.
• an antibody is administered intravenously and the therapeutic agent is administered orally (e.g., exemestane)
• their combination is preferably administered as two separate pharmaceutical compositions.
• the present invention also encompasses the administration of other therapeutic agents in addition to the antibody and first therapeutic agent, either concurrently with one or more of those components, or sequentially before and/or after.
• therapeutic agents include cancer vaccines, anti-vascular agents, anti-proliferative agents, antiagionesis agents, signal transduction inhibitors, immunomodulatory agents, cytokines, and palliative agents to provide supportive care, such as, but not limited to, analgesics, anti-emetic agents, anti- diarrheal agents, and steroids.
• Preferred anti-emetic agents include ondansetron hydrochloride, granisetron hydrochloride, and metoclopramide.
• Preferred anti-diarrheal agents include diphenoxylate and atropine (LOMOTIL), loperamide (IMMODIUM) 1 octreotide (SANDOSTATIN), olsalazine (DIPENTUM), and mesalamine (ASACOL).
• Preferred steroids include the non-absorbable steroid budesonide (ENTOCORT), and the steroids for systemic administration dexametasone (DECADRON) and prednisone (METICORTEN). Each administration may vary in its duration from a rapid administration to a continuous perfusion.
• compositions according to the invention are preferably compositions which can be administered parentally. However, these compositions may be administered orally or intraperitoneally in the case of localized regional therapies.
• the methods of the present invention are suitable for use both as first line therapy and second line therapy. Treatment of both early stage and advanced (metastatic) cancers are within the scope of the present invention.
• the invention encompasses the preparation and use of pharmaceutical compositions comprising a human anti-CTLA4 antibody of the invention as an active ingredient in combination with a therapeutic agent, e.g., a chemotherapeutic agent, another antibody, an immunostimulatory agent, a signal transduction inhibitor, an angiogenesis inhibitor, preferably, the therapeutic agent is a chemotherapeutic agent.
• a therapeutic agent e.g., a chemotherapeutic agent, another antibody, an immunostimulatory agent, a signal transduction inhibitor, an angiogenesis inhibitor
• the therapeutic agent is a chemotherapeutic agent.
• Such a pharmaceutical composition may consist of each active ingredient alone, as a combination of at least one active ingredient (e.g., an effective dose of an anti-CTLA4, an effective does of a therapeutic agent) in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional (active and/or inactive) ingredients, or some combination of these.
• the antibody is administered parenterally (e.g., intravenously) in an aqueous solution while the therapeutic agent (e.g., a chemotherapeutic agent, a signal transduction inhibitor, an immunomodulator, an angiogenesis inhibitor, and the like) is administered orally in pill/capsule form.
• the therapeutic agent e.g., a chemotherapeutic agent, a signal transduction inhibitor, an immunomodulator, an angiogenesis inhibitor, and the like
• the invention is not limited to these, or any other, formulations, doses, routes of administration, and the like.
• the invention encompasses any formulation or method of administering an antibody in combination with a therapeutic agent, including, but not limited to, administering each agent separately in a different formulation via a different route of administration, and administering the antibody and the therapeutic agent in a single composition (e.g. where the therapeutic agent is a protein, such as, another antibody, a cytokine, a costim, and the like), in an aqueous composition administered, inter alia, intravenously), among many others.
• a therapeutic agent is a protein, such as, another antibody, a cytokine, a costim, and the like
• the antibodies may be present in a neutral form (including zwitter ionic forms) or as a positively or negatively-charged species. In some embodiments, the antibodies may be complexed with a counterion to form a pharmaceutically acceptable salt.
• pharmaceutically acceptable salt refer to a complex comprising one or more antibodies and one or more counterions, where the counterions are derived from pharmaceutically acceptable inorganic and organic acids and bases.
• Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, cobalt, nickel, molybdenum, vanadium, manganese, chromium, selenium, tin, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, rubidium, sodium, and zinc, and in their usual valences.
• compositions of the antibodies of the present invention can be prepared from the following acids, including, without limitation formic, acetic, acetamidobenzoic, adipic, ascorbic, boric, propionic, benzoic, camphoric, carbonic, cyclamic, dehydrocholic, malonic, edetic, ethylsulfuric, fendizoic, metaphosphoric, succinic, glycolic, gluconic, lactic, malic, tartaric, tannic, citric, nitric, ascorbic, glucuronic, maleic, folic, fumaric, propionic, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, lysine, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, orotic, oxalic, oxalacetic, oleic
• Organic bases include trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, dibenzylamine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, cyclic amines, quaternary ammonium cations, arginine, betaine, caffeine, clemizole, 2-ethylaminoethanol, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanediamine, butylamine, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, ethylglucamine, glucamine, glucosamine, histidine, hydrabamine, imidazole, isopropylamine, methylglucamine, morpholine, piperazine, pyridine, pyridoxine, neodymium, piperidine, polyamine resin
• the anti-CTLA4 antibody used in the methods of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject.
• the pharmaceutical composition comprises the antibody and a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
• pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
• isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
• Pharmaceutically acceptable substances such as wetting or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
• the antibodies and therapeutic agents used in the present invention may be in a variety of forms. These include, for example, liquid, semi solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
• the preferred form depends on the therapeutic agent, the intended mode of administration and the therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
• the preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
• the antibody is administered by intravenous infusion or injection.
• the antibody is administered by intramuscular or subcutaneous injection.
• compositions typically must be sterile and stable under the conditions of manufacture and storage.
• the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
• Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum drying and freeze drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile filtered solution thereof.
• the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
• the antibodies can be administered by a variety of methods known in the art, including, without limitation, oral, parenteral, mucosal, by-inhalation, topical, buccal, nasal, and rectal.
• the preferred route/mode of administration is subcutaneous, intramuscular, intravenous or infusion. Non-needle injection may be employed, if desired.
• the route and/or mode of administration will vary depending upon the desired results.
• the antibody may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
• a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York (1978).
• Transdermal delivery of biological molecules includes microneedles to create micron-sized temporary transport pathways in the skin through which large molecules can be transported. See, e.g., Banga, In: Therapeutic peptides and proteins: Formulation, processing and delivery systems, 2 nd ed., Taylor & Francis (Eds.), 2006; Martanto et al., J. Controlled Release 112:357-361 (2006).
• microneedles include those composed of silicon, metal or a polymer.
• maltose microneedles which dissolve in the skin may be used to administered the compositions of the invention, including anti-CTLA4 antibody, anti-CD40, anti-IGF-1R antibody, rituximab, trastuzumab, IL-15, and the like.
• nucleic acid including nucleic acids encoding a protein, preferably, anti-CTLA4 antibody (e.g., CP-675,206, ipilimumab, and the like), or an ODN
• a protein preferably, anti-CTLA4 antibody (e.g., CP-675,206, ipilimumab, and the like)
• an ODN can be delivered transdermal ⁇ using biolistics to provide expression of the antibody or delivery of the ODN in a micromilieu where antigen presenting cells (e.g., dendritic cells) and/or T regulatory cells are present (e.g., Tregs in lymph nodes).
• antigen presenting cells e.g., dendritic cells
• T regulatory cells e.g., Tregs in lymph nodes
• Gold microparticles comprising nucleic acids encoding anti-CTLA4 antibody and/or comprising an ODN or nucleic acids encoding a protein of interest, are propelled through the skin using, for example, a "gene gun” (PMED Device, e.g., model ND-10, PowderMed Ltd., Oxford, UK). See, e.g., US Patent Nos. 6,194,389; 6,168,587; 5,478,744.
• a synthetic oligodeoxynucleotide (ODN) toll-like receptor 9 agonist may be administered using biolistics such that a microparticle comprising the nucleic acid encoding the antibody and a microparticle comprising the ODN, or a microparticle comprising both, are both delivered transdermally.
• a nucleic acid encoding a TAA e.g., gplOO, tyrosinase, MAGE, MART-1 , NY- ESO-1, and the like
• TAA is delivered transdermally using biolistics such that the TAA is expressed in and presented by APCs transfected with the nucleic acid.
• an antigen e.g., TAA
• an antibody anti-CTLA4, anti-CD40, anti-CD20, anti-HER2, etc.
• a cytokine e.g., GM-CSF, IL-15, TNF ⁇ , among others
• an ODN e.g., PF03512676
• a costimulatory molecule e.g., PD-1, OX40, 4-1BB, etc.
• Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
• the antibody is administered in a formulation as a sterile aqueous solution having a pH that ranges from about 5.0 to about 6.5 and comprising from about 1 mg/ml to about 200 mg/ml of antibody, from about 1 millimolar to about 100 millimolar of histidine buffer, from about 0.01 mg/ml to about 10 mg/ml of polysorbate 80, from about 100 millimolar to about 400 millimolar of trehalose, and from about 0.01 millimolar to about 1.0 millimolar of disodium EDTA dihydrate.
• Exemplary formulations encompass, but are not limited to, such formulations described in PCT/US2006/007551 filed March 2, 2006, now published as WO 2006/096488 on Sept. 14, 2006, and PCT/US2006/007555 filed March 2, 2006, now published as WO 2006/096491 on Sept. 14, 2006.
• the antibody is administered in an intravenous formulation as a sterile aqueous solution containing 5 mg/m, or more preferably, about 10 mg/ml, or yet more preferably, about 15 mg/ml, or even more preferably, about 20 mg/ml of antibody, with sodium acetate, polysorbate 80, and sodium chloride at a pH ranging from about 5 to 6.
• the intravenous formulation is a sterile aqueous solution containing 5 or 10 mg/ml of antibody, with 20 mM sodium acetate, 0.2 mg/ml polysorbate 80, and 140 mM sodium chloride at pH 5.5.
• a solution comprising an anti-CTLA4 antibody can comprise, among many other compounds, histidine, mannitol, sucrose, trehalose, glycine, poly(ethylene) glycol, EDTA, methionine, and any combination thereof, and many other compounds known in the relevant art.
• compositions of the present invention optionally may further comprise a pharmaceutically acceptable antioxidant in addition to a chelating agent.
• Suitable antioxidants include, but are not limited to, methionine, sodium thiosulfate, catalase, and platinum.
• the composition may contain methionine in a concentration that ranges from 1 mM to about 100 mM, and in particular, is about 27 mM.
• part of the dose is administered by an intraveneous bolus and the rest by infusion of the antibody formulation.
• a 0.01 mg/kg intravenous injection of the antibody may be given as a bolus, and the rest of a predetermined antibody dose may be administered by intravenous injection.
• a predetermined dose of the antibody may be administered, for example, over a period of an hour and a half to two hours to five hours.
• a therapeutic agent where the agent is, e.g., a small molecule, it can be present in a pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
• compositions of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
• Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, or another route of administration.
• Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
• a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
• the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
• compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active therapeutic agents.
• additional agents include anti-emetics, anti-diarrheals, chemotherapeutic agents, cytokines, and the like.
• Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
• a formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient.
• Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.
• an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
• a tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients.
• Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent.
• Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
• compositions used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
• Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate.
• Known surface active agents include, but are not limited to, sodium lauryl sulphate.
• Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate.
• Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.
• binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
• Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
• Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient.
• a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
• tablets may be coated using methods described in U.S. Patents numbers 4,256,108; 4,160,452; and 4,265,874 to form osmotically-controlled release tablets.
• Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation.
• Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
• an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
• Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin.
• Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
• Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
• Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle.
• Aqueous vehicles include, for example, water and isotonic saline.
• Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
• Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.
• Oily suspensions may further comprise a thickening agent.
• suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose.
• Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively).
• Known emulsifying agents include, but are not limited to, lecithin and acacia.
• Known preservatives include, but are not limited to, methyl, ethyl, or n- propyl-para-hydroxybenzoates, ascorbic acid, and sorbic acid.
• Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
• Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.
• Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent.
• Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent.
• Aqueous solvents include, for example, water and isotonic saline.
• Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
• Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
• a pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion.
• the oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these.
• compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
• emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration.
• a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.
• Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e., about 2O 0 C) and which is liquid at the rectal temperature of the subject (i.e., about 37°C in a healthy human).
• Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides.
• Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.
• Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
• enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for vaginal administration. Such a composition may be in the form of, for example, a suppository, an impregnated or coated vaginally-insertable material such as a tampon, a douche preparation, or gel or cream or a solution for vaginal irrigation.
• Methods for impregnating or coating a material with a chemical composition include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e. such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.
• Douche preparations or solutions for vaginal irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
• douche preparations may be administered using, and may be packaged within, a delivery device adapted to the vaginal anatomy of the subject.
• Douche preparations may further comprise various additional ingredients including, but not limited to, antioxidants, antibiotics, antifungal agents, and preservatives.
• parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
• Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
• parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
• Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations as discussed below.
• Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
• the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
• a composition of the present invention can be administered by a variety of methods known in the art.
• the route and/or mode of administration vary depending upon the desired results.
• the active compounds can be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, (1978).
• Pharmaceutical compositions are preferably manufactured under GMP conditions.
• compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
• This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
• Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1 ,3-butane diol, for example.
• Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
• compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
• Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
• Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
• Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity.
• a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers.
• Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container.
• such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
• Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
• Low boiling propellents generally include liquid propellants having a boiling point of below 65°F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
• the propellant may further comprise additional ingredients such as a liquid non- ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
• compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension.
• Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device.
• Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate.
• the droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
• formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.
• Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers.
• Such a formulation is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
• Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration.
• Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein.
• formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient.
• Such powdered, aerosolized, or aerosolized formulations, when dispersed preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration.
• Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily liquid carrier.
• Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein.
• Other ophthalmalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.
• additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
• compositions of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences, Genaro, ed., Mack Publishing Co., Easton, PA (1985), which is incorporated herein by reference.
• the composition comprising CP-675,206 comprises a sterile solution comprising 20 mM histidine buffer, pH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA hydrate.
• CP-675,206 is packaged in clear glass vials with a rubber stopper and an aluminum seal.
• the vial contains about 20 mg/ml of CP-675,206 with a nominal fill of about 400 mg per vial.
• the anti-CTLA4/therapeutic agent active ingredient combination of the invention can be administered to an animal, preferably a human.
• each active ingredient administered will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal and the route of administration.
• the anti-CTLA4 antibody may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less.
• the frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.
• the therapeutic agent preferably, a chemotherapeutic agent
• the frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.
• the antibody and therapeutic agent can be co-administered in that they can be administered separately, on different dates or at different times of the day, as well as simultaneously or on the same date. Co-administration thus encompasses any temporal combination of administration of the antibody and the therapeutic agent such that administration of the two agents mediates a therapeutic benefit to the patient that is detectably greater than administration of either agent in the absence of the other.
• An antibody-therapeutic agent combination of the invention may be co-administered with numerous other compounds (other antihormonal therapy agents, cytokines, chemotherapeutic and/or antiviral drugs, among many others).
• the compound(s) may be administered an hour, a day, a week, a month, or even more, in advance of the antibody-therapeutic agent combination, or any permutation thereof.
• the compound(s) may be administered an hour, a day, a week, or even more preferably, after administration of radiation, stem cell transplant, or administration of any therapeutic agent (e.g., cytokine, chemotherapeutic compound, and the like), or any permutation thereof.
• the frequency and administration regimen will be readily apparent to the skilled artisan and will depend upon any number of factors such as, but not limited to, the type and severity of the disease being treated, the age and health status of the animal, the identity of the compound or compounds being administered, the route of administration of the various compounds, and the like.
• kits which comprise a therapeutically effective amount of a human anti-CTLA4 antibody of the invention and a therapeutically effective amount of a therapeutic agent, along with an applicator and instructional materials which describe use of the combination to perform the methods of the invention.
• exemplary kits are described below, the contents of other useful kits will be apparent to the skilled artisan in light of the present disclosure. Each of these kits is included within the invention.
• the invention includes a kit for treatment of breast cancer in a patient in need thereof.
• the kit includes a human anti-CTLA4 antibody of the invention and at least one therapeutic agent.
• the inhibitor encompasses, but is not limited to, a chemotherapeutic, an antibody, a cytokine, a vaccine, an immunomodulator, among many others.
• the kit further comprises an applicator, including, but not limited to, a syringe, for administration of the components of the kit to a patient.
• the kit comprises an instructional material setting forth the pertinent information for the use of the kit to treat breast cancer in the patient.
• the kit comprises at least one anti-CTLA4 antibody selected from an antibody having the heavy and light chain amino acid sequence of antibody 4.1.1 , 4.8.1 , 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1 (CP-675,206), 11.6.1 , 11.7.1., 12.3.1.1, 12.9.1.1 , and ipilimumab, even more preferably, the antibody is an antibody having the heavy and light chain amino acid sequence of antibody 4.13.1 , 11.2.1 (CP-675,206), and ipilimumab (MDX- 010).
• the antibody is an antibody having the heavy and light sequence of 11.2.1 (CP-675,206).
• the anti-CTLA4 antibody is CP-675,206 or ipilimumab. Most preferably, the antibody is CP-675,206.
• the kit can comprise any number of additional therapeutic agents for treatment of cancer.
• agents are set forth previously and include chemotherapeutic compounds, cancer vaccines, signal transduction inhibitors, agents useful in treating abnormal cell growth or cancer, antibodies or other ligands that inhibit tumor growth by binding to IGF-1R, and cytokines, among many others.
• the invention also relates to an article of manufacture (e.g., dosage form adapted for i.v. administration) comprising a human anti-CTLA4 antibody in the amount effective to treat cancer (e.g., more than 10 mg/kg, at least 15 mg/kg, or 15 mg/kg) and a therapeutically effective amount of a second therapeutic agent.
• the article of manufacture comprises a container or containers comprising a human anti-CTLA4 antibody, the therapeutic agent, and a label and/or instructions for use to treat cancer.
• the therapeutic agent is at least one agent selected from a hormonal therapy agent, a taxane, a heat shock protein, a topoisomerase inhibitor, a hormonal therapy agent (e.g., leuprolide), a chemotherapeutic compounds, a vinca alkaloid, a platinum compound, a cancer vaccine, a tumor-specific antigen, an angiogenesis inhibitor, a signal transduction inhibitor, agents useful in treating abnormal cell growth or cancer, antibodies or other ligands that inhibit tumor growth by binding to IGF-1 R, and cytokines, among others.
• the kit can comprise any number of additional therapeutic agents for treatment of cancer.
• Such agents are set forth previously and include chemotherapeutic compounds, cancer vaccines, signal transduction inhibitors, agents useful in treating abnormal cell growth or cancer, antibodies or other ligands that inhibit tumor growth by binding to IGF-1 R, and cytokines, and palliative care agents (e.g., anti-diarrheals, anti-emetics, etc.) among many others.
• the kit is for treatment of breast cancer.
• the kit comprises an anti-CTLA4 antibody and a taxane.
• the taxane is docetaxel or paclitaxel.
• the treatment is first line therapy for the treatment of patients with locally advanced or metastatic triple receptor negative breast cancer.
• the kit is for treatment of ovarian cancer.
• the kit comprises an anti-CTLA4 antibody and a therapeutic agent, where the therapeutic agent is paclitaxel.
• the kit further comprises carboplatin.
• the kit is for first-line treatment of advanced carcinoma of the ovary.
• the kit is for second line treatment of a patient who has progressed following prior paclitaxel-based therapy.
• the kit is for treatment of non-small cell lung cancer.
• the kit comprises an anti-CTLA4 antibody and a chemotherapeutic agent, wherein the therapeutic agent is selected from the group consisting of a platin (e.g., carboplatin (PARAPLATIN), paclitaxel (TAXOL)), docetaxel (TAXOTERE), sunitinib (SU11248), erlotinib (TARCEVA), bevacizumab (AVASTIN), pemetrexed (ALIMTA), and PF03512676 (CpG-7909).
• a platin e.g., carboplatin (PARAPLATIN), paclitaxel (TAXOL)), docetaxel (TAXOTERE), sunitinib (SU11248), erlotinib (TARCEVA), bevacizumab (AVASTIN), pemetrexed (ALIMTA), and PF03512676 (CpG-7909).
• kit is for first line therapy of locally advanced Stage IMb or metastatic Stage IV NSCLC where the kit comprises an anti-CTLA4 antibody and a platin.
• the kit comprises carboplatin and paclitaxel.
• the kit comprises the antibody and bevacizumab.
• the kit comprises the antibody and PF03512676.
• the kit comprises the antibody and sunitinib.
• the kit is for second line treatment of Stage IHb or metastatic Stage IV NSCLC after failure of platinum-based therapy.
• the kit comprises an anti-CTLA4 antibody and docetaxel.
• the kit comprises the antibody and erlotinib.
• the kit comprises the antibody and pemetrexed.
• the kit comprises an anti-CTLA4 antibody.
• the kit is for third line treatment of locally advanced Stage IHb or metastatic Stage IV NSCLC.
• the kit comprises an effective amount of an anti-CTJ_A4 antibody.
• the kit is for treatment of cancer after failure of prior platinum-based chemotherapy and EGFR inhibition-based therapy.
• the kit is for treatment of pancreatic cancer.
• the kit comprises an anti-CTLA4 antibody and a therapeutic agent, wherein the agent is gemcitabine.
• the treatment is first line therapy for locally advanced, non-resectable Stage Il or
• Stage III or metastatic Stage IV adenocarcinoma of the pancreas.
• the kit is for treatment of melanoma and comprises an effective amount of an anti-CTLA4 antibody and an effective amount of IFN ⁇ .
• the treatment is adjuvant therapy for Stage ll/lll melanoma.
• the kit is for treatment of colorectal carcinoma.
• the kit comprises an effective amount of an anti-CTLA4 antibody and an effective amount of each of fluorouracil, leucovorin and oxaliplatin (FOLFOX).
• the kit comprises an effective amount of an anti-CTLA4 antibody, fluorouracil, leucovorin and irinotecan (FOLFIRI).
• the treatment is first line therapy for metastatic CRC.
• the therapy is adjuvant therapy for Stage III colon cancer in a patient who has undergone resection of a primary tumor.
• the kit is for treatment of CRC and comprises an effective amount of an anti-CTLA4 antibody and an effective amount of capecitabine (XELODA).
• the treatment is first line therapy for a patient intolerant of therapy comprising oxaliplatin (ELOXATIN) or irinotecan (CAMPTOSAR).
• NDLs Indolent Non-Hodgkin's Lymphomas
• NHL low grade and some categories of intermediate grade NHL in the Working Formulation.
• Non-Hodgkin's lymphoma (NHL) with at least one lesion that can be accurately measured in two dimensions and whose size is ⁇ 2 cm x 1 cm by conventional CT scan or ⁇ 1 cm x 1 cm by spiral CT scan are given standard rituximab (RITUXAN) antibody therapy per established protocols.
• CP-675,206 is administered at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of CP-675,206 dose, that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every 28 days thereafter for maximum of 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• Rituximab is administered via intravenous infusion at about 375 mg/m 2 once weekly for about four or eight doses. More preferably, rituximab is administered on day 1 of each cycle of chemotherapy.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of either antibody. Premedication is recommended but not required.
• H1 antihistamine
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• Rituximab and anti-CTLA4 antibody are administered either sequentially or simultaneously either once, or repeatedly, as determined.
• anti-CTLA4 antibody is administered as single agent (SA) therapy as described supra for combination therapy.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG Eastern Cooperative Oncology Group performance status
• PS vital signs
• body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• hematocrit hematocrit, RBC count, WBC count, differential
• chemistry Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose. The following endpoints are measured: PK parameters, HAHA, response rate and time to progression. Time to progression and overall survival are calculated using the Kaplan-Meier product limit method.
• Patients having aggressive, CHOP-R refractory NHL with at least one lesion that can be accurately measured in two dimensions and whose size is ⁇ 2 cm x 1 cm by conventional CT scan or ⁇ 1 cm x 1 cm by spiral CT scan are given standard rituximab antibody therapy per established protocols.
• the patient is further administered a single IV infusion (100 mL/hr) of CP-675,206 as described herein at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti- CTLA4 antibody dose, that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every 28 days thereafter for maximum of 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• the patient is administered rituximab according to an art-recognized dosing regimen.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4.
• H1 antihistamine
• Premedication is recommended but not required.
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• Rituximab e.g., RITUXAN
• the anti-CTLA4 antibody are administered either sequentially or simultaneously either once, or repeatedly, as determined.
• CTLA4 antibody is administered as described supra.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• chemistry Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose,
• HAHA human anti-human antibody
• PK pharmacokinetic
• PK parameters PK parameters
• HAHA response rate
• time to progression are calculated using the Kaplan-Meier product limit method.
• CRC colorectal carcinoma
• ELOXATIN oxaliplatin
• CAMPTOSAR irinotecan
• the patient is further administered a single IV infusion (100 mL/hr) of CP-675,206 as described herein at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti-
• CTLA4 antibody dose that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every 28 days thereafter for maximum of 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• H1 antihistamine
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• Capecitabine for second line therapy or 5-fluorouracil for adjuvant therapy is administered sequentially or simultaneously with CP-675,206 either once, or repeatedly, as determined.
• Capecitabine and fluorouracil are administered according to well-known protocols, for examples, those disclosed in the FDA-approved label for each compound.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• chemistry Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose,
• HAHA human anti-human antibody
• PK pharmacokinetic
• PK parameters PK parameters
• HAHA response rate
• time to progression are calculated using the Kaplan-Meier product limit method.
• CRC colorectal carcinoma
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti-CTLA4 antibody dose, that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• FOLFOX or FOLFIRI therapy is administered according to standard protocols. Briefly, for FOLFOX4, each chemotherapy cycle comprises a two hour infusion of 85 mg/m 2 oxaliplatin (ELOXATIN, Sanofi) on day 1 followed by a two hour infusion of 200 mg/m 2 leucovorin on days 1 and 2, followed by a bolus of 400 mg/m 2 of fluorouracil on days 1 and 2 and then a twenty-two hour infusion of 600 mg/m 2 of fluorouracil administered over two consecutive days (referred to as the De Gramont schedule). Chemotherapy is repeated every two weeks.
• ELOXATIN 85 mg/m 2 oxaliplatin
• FOLFIRI is administered as a ninety minute infusion of 180 mg/m 2 irinotecan on day 1, a two hour infusion of folinic acid (leucovorin) at 400 mg/m 2 on day 1 , and 400-500 mg/m 2 fluorouracil IV bolus after leucovorin on day 1, followed by fluorouracil at 2400-3000 mg/m 2 by continuous i.v. over forty-six hours starting on day one.
• the chemotherapy cycle is repeated every two weeks.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• FOLFOX therapy is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose.
• PK parameters PK parameters
• HAHA response rate
• time to progression are calculated using the Kaplan-Meier product limit method.
• CP-675.206 and Gemcitabine for Treatment of Pancreatic Cancer Following surgery/radiotherapy, if any, patients having pancreatic cancer with at least one lesion that can be accurately measured in two dimensions and whose size is ⁇ 2 cm x 1 cm by conventional CT scan or ⁇ 1 cm x 1 cm by spiral CT scan are given standard chemotherapy comprising gemcitabine (e.g., GEMZAR) per established protocols.
• gemcitabine e.g., GEMZAR
• the patient is further administered a single IV infusion of anti-CTLA4 antibodies as described herein at a dose of at least about 10 mg/kg, preferably, at about 15 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti-CTLA4 antibody dose, if desired, every 28 days thereafter for maximum of 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• Gemcitabine is administered according to standard protocols. More particularly, gemcitabine (GEMZAR, Lilly) is administered by intravenous infusion at a dose of 1000 mg/m 2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose) followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks . CP-675,206 is administered after the initial gemcitabine cycle (seven weeks on and one week rest) and once every three weeks thereafter.
• GEMZAR gemcitabine
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• H1 antihistamine
• antibody dose is escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• HAHA human anti-human antibody
• PK pharmacokinetic
• PK parameters PK parameters
• HAHA response rate
• time to progression are calculated using the Kaplan-Meier product limit method.
• CML chronic myeloid leukemia
• GLEEVEC imatinib mesylate
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti-CTLA4 antibody dose, that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• Imatinib mesylate (GLEEVEC, Novartis) is administered daily at about 400 mg/day for patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. Imatinib treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days. lmatinib mesylate is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose.
• CLL chronic lymphocytic leukemia
• GLEEVEC imatinib mesylate
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti-CTLA4 antibody dose, that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every 28 days thereafter for maximum of 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• Imatinib mesylate GLEEVEC, Novartis
• GLEEVEC Novartis
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• Imatinib mesylate GLEEVEC, Novartis
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4.
• H1 antihistamine
• Premedication is recommended but not required.
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• GLEEVEC is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTTj, prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose.
• Patients having advanced carcinoma of the ovary are given standard chemotherapy using carboplatin and paclitaxel per established protocols.
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 3 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days with escalation of the anti-CTLA4 antibody dose, that is, 6 mg/kg, 10 mg/kg and 15 mg/kg, every 28 days thereafter for maximum of 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• paclitaxel is administered every three weeks at 175 mg/m 2 by i.v. infusion over ninety minutes followed by carboplatin (area under the time-concentration curve [AUC] of 5) administered i.v. over thirty to sixty minutes.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• H1 antihistamine
• Doses are escalated using an accelerated titration design utilizing a dose-doubling schema with 3-6 subjects per cohort. Within each new cohort there is no required waiting period between subjects. Subsequent cohorts may not be opened until the first subject at the current dose level has been observed for 21 days and subsequent subjects have been observed for 14 days.
• Carboplatin and paclitaxel combination is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose.
• CP-675,206 in Combination with carboplatin and paclitaxel and either bevacizumab.
• Patients having locally advanced Stage IHb or mestatatic Stage IV NSCLC are given standard chemotherapy using carboplatin and paclitaxel per established protocols.
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 15 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days for approximately 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• bevacizumab (AVASTIN), PF03512676, or sunitinib per established protocols.
• Bevacizumab may be administered at about 5 mg/kg every fourteen days by i.v. infusion until disease progression is detected.
• Sunitinib may be administered as one 50 mg oral dose taken daily, on a schedule of four weeks on treatment followed by two weeks off. Sunitinib may be taken with or without food. Dose increase or reduction of 12.5 mg increments is recommended based on individual safety and tolerability.
• An exemplary carboplatin and paclitaxel dosing regimen is as provided supra.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• H1 antihistamine
• Carboplatin and paclitaxel combination is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• bevacizumab, sunitinib, or PF03512676 is administered sequentially or simultaneously with anti-CTLA4- carboplatin-paclitaxel, either once, or repeatedly, as indicated.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal.
• Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination is performed on Day 1.
• Samples for hematology panel hematocrit, RBC count, WBC count, differential
• chemistry Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein,
• TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• HAHA human anti-human antibody
• PK pharmacokinetic
• Patients having locally advanced Stage IHb or mestatatic Stage IV NSCLC, and which have previously failed platinum-based chemotherapy, are given standard chemotherapy using one of either docetaxel (TAXOTERE), erlotinib (TARCEVA), or pemetrexed (ALIMTA) per established protocols.
• TXOTERE docetaxel
• TARCEVA erlotinib
• ALOMTA pemetrexed
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 15 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days for approximately 12 cycles in the absence of intolerable toxicity or disease progression.
• CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• Docetaxel (TAXOTERE, Sanofi-Aventis) is administered at about 75 mg/m 2 by i.v. infusion over one hour every three weeks.
• Erlotinib (TARCEVA, OSI Pharms.) is administered as a daily dose of about 150 mg taken at least one hour or two hours after ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs.
• Pemetrexed (ALIMTA, Lilly) is administered at a dose of about 500 mg/m 2 administered as an i.v. infusion over 10 minutes on day 1 of each 21 -day cycle.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• Docetaxel, erlotinib or pemetrexed is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose.
• PK parameters PK parameters
• HAHA 1 response rate HAHA 1 response rate
• time to progression are calculated using the Kaplan-Meier product limit method.
• Patients having advanced Stage MIb (with effusion) or mestatatic Stage IV NSCLC, and which have previously responded or remained stable after a platinum-based chemotherapy first line regimen, are given CP-675,206 at least about three weeks but not more than about six weeks after the lose of first line platinum-based therapy.
• the patient is further administered a single IV infusion (100 mL/hr) of anti-CTLA4 antibodies as described herein at a dose of about 15 mg/kg.
• Prophylactic anti-emetics and anti-diarrheals are given as appropriate.
• the treatment is repeated after 28 days for approximately 12 cycles in the absence of intolerable toxicity or disease progression. More preferably, CP-675,206 is administered at at least about 10 mg/kg every three weeks for four cycles and then every three months thereafter.
• the patient is premedicated with antihistamine (H1) at least one half hour prior to infusion of anti-CTLA4. Premedication is recommended but not required.
• H1 antihistamine
• Docetaxel, erlotinib or pemetrexed is administered sequentially or simultaneously with anti-CTLA4 antibody either once, or repeatedly, as determined.
• CP-675,206 is provided in 20 ml clear glass vials with a rubber stopper and an aluminum seal. Each vial contains 20 mg/ml (with a nominal fill of 400 mg/vial) of CP- 675,206, in a sterile aqueous solution comprising 20 mM histidine buffer, PH 5.5, 84 mg/ml trehalose dehydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dehydrate.
• ECOG performance status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated post-dose, as clinically indicated.
• a physical examination (including ophthalmologic assessment and signs of autoimmunity) is performed on Day 1.
• Samples for hematology panel (hematocrit, RBC count, WBC count, differential), chemistry (Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urinalysis (blood, protein), others (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig level), are obtained.
• chemistry Alkaline Phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose,
• Baseline human anti-human antibody (HAHA) titer is determined and pharmacokinetic (PK) specimen is obtained pre-dose. The following endpoints are measured: PK parameters, HAHA, response rate and time to progression. Time to progression and overall survival are calculated using the Kaplan-Meier product limit method.
• Diarrhea (all grades) occurred with similar frequency in each dose group; however, grade 3 treatment-related diarrhea occurred in 8% of patients treated with 15 mg/kg Q3M compared with 18% of patients treated with 10 mg/kg Q1M in phase I and 14% of patients treated with 10 mg/kg Q1M in phase II.
• 8 experienced diarrhea (3 of which were grade 3).
• Diarrhea associated with CP-675,206 was primarily mild to moderate in severity, transient, and manageable.
• 15 mg/kg Q3M may be better tolerated than 10 mg/kg Q1 M.
• EXAMPLE 13 Survival of patients with metastatic melanoma treated with anti-CTLA4 monoclonal antibody CP-675,206 in a phase l/ll study CP-675,206 has demonstrated clinical activity in patients with metastatic melanoma. Prolonged survival was observed in a prior single-dose phase I study, even in patients who did not achieve objective tumor responses.
• the study consisted of a phase I, open-label, multidose study (3, 6, and 10 mg/kg) and a phase I expansion cohort for HLA-A2.1 + patients (10 mg/kg monthly [10Q1 M]), followed by a phase Il open-label study of 2 dosing regimens: 10 mg/kg Q1M and 15 mg/kg every 3 months (15Q3M).
• the primary endpoint was safety in phase I, immune monitoring in the expansion cohort, and response in phase II. Survival was analyzed as a secondary endpoint.
• stage IUc or IV Eligible patients had measurable melanoma progressing on or after prior therapy with ECOG PS ⁇ 1.
• stage 1 18 patients per arm were randomized to either 10 mg/kg once per month (10Q1M) or 15 mg/kg every 3 months (15Q3M). If 3 or more patients in either arm had complete response (CR) or partial response (PR), then 25 more patients were entered to that arm.
• Primary endpoint was objective tumor response (OR), and secondary endpoints were safety and survival.
• Two patients at 15Q3M were discontinued: one due to colitis and pancreatitis, and the other due to diarrhea (P 0.14). There were no toxic deaths.
• AEs adverse events
• the 1998- 99 vaccine contained hemagglutinin A (HA) from three strains: A/Beijing/262/95 (H1N1 ), A/Sydney/5/97 (H3N2), and B/Harbin/07/94 (a B/Beijing/184/93-like strain).
• HA hemagglutinin A
• the monkeys were immunized intramuscularly (IM) with FLUZONE on day 0 (week 0) and again 4 weeks later (week 4).
• Antibody was administered according to the following schedule: Group 1 was administered anti-CTLA4 antibody CP-642,570 (5 mg/kg) intravenously (IV) on week 0; Group 2 was administered an irrelevant control antibody (anti-KLH antibody; 5 mg/kg IV) on week 0; Group 3 was immunized IM with FLUZONE on week 0 and reimmunized IM with FLUZONE on week 4 and administered anti-CTLA4 antibody (5 mg/kg IV) on week 4; Group 4 was immunized IM with FLUZONE on week 0 and reimmunized IM with FLUZONE on week 4 and administered an irrelevant control antibody (anti-KLH antibody at 5 mg/kg IV) on week 4; and Group 5 was immunized IM with FLUZONE on week 0 and reimmunized IM with FLUZONE on week 4 but no antibody was administered. The animals were followed for eight weeks after the initial immunization with FLUZONE.
• the anti-CTLA4 antibody administered was human anti-human CTLA4 designated CP-642,570 (also referred to herein as antibody 4.1.1).
• Serum was collected at 1 hour and 24 hours after anti-CTLA4 administration and every two weeks thereafter. The following parameters were assessed: anti-CTLA4 serum levels, IgG titers to FLUZONE, level of Neopterin, and level of 2-5 adenylate synthetase.
• Plasma levels of anti-CTLA4 antibody confirmed exposure, i.e., plasma levels were approximately 75 ⁇ g/ml at 1 hour, 40-50 ⁇ g/ml at 24 hours and, for the most part, not detectable by two weeks (Figure 4).
• Plasma levels of anti-CTLA4 antibody confirmed exposure, i.e., plasma levels were approximately 75 ⁇ g/ml at 1 hour, 40-50 ⁇ g/ml at 24 hours and, for the most part, not detectable by two weeks (Figure 4).
• One animal in Group 3 had undetectable levels of antibody, possibly due to a missed injection or a switched tube.
• the animals were assessed for various markers of immune activation. Neopterin levels were variable (Figure 5). That is, an initial spike in value was detected in the anti- CTLA4 group two weeks post-immunization and treatment. Four weeks after immunization, the basal levels dropped and no differences were observed between the groups, including groups 3 and 4.

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