JP2007277242A - Ctla4 antibody combination therapy - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide administration of human antibody, particularly human antibodies to human CTLA4, such as those having amino acid sequences 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, 12.9.1.1, CP-675,206 (11.2.1) and ipilimumab, in combination with a therapeutic agent for treatment of cancer. <P>SOLUTION: An exemplary method of the invention comprises a step for administering an anti-CTLA4 antibody, preferably, CP-675,206, and a chemotherapeutic agent, preferably, gemcitabine for treatment of pancreatic cancer, among other treatment modalities. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to uses and compositions comprising an anti-CTLA4 antibody and at least one therapeutic agent for treating cancer. In addition to the combined use of antibodies and therapeutic agent inhibitors, the present invention further relates to, among other things, providing additional therapeutic agents, at least one additional therapy, such as radiation or stem cell transplantation.

  Current anti-tumor agents work by various mechanisms that inhibit the growth and division of cancer cells, eventually destroying malignant cells. However, since this cytotoxic agent is generally not selective for tumor cells, the agent destroys normal cells, disrupts physiological functions and often leads to adverse effects. An alternative approach to cancer treatment is to target the immune system rather than the tumor itself (“immunotherapy”) so that the patient's own immune system attacks the tumor while leaving non-tumor cells.

  One approach to cancer immunotherapy targets cytotoxic T lymphocyte associated antigen 4 (CTLA4; CD152), a cell surface receptor expressed on activated T cells. When CTLA4 binds to its natural ligands B7.1 (CD80) and B7.2 (CD86), a negative regulatory signal is delivered to the T cell, and blocking this negative signal results in T cell immunity in animal models. Function and antitumor activity are enhanced (Thompson and Allison, Immunity 7: 445-450 (1997); McCoy and LeGros, Immunol. & Cell Biol. 77: 1-10 (1999)). Several studies have shown that blocking CTLA4 using antibodies markedly enhances T cell-mediated tumor killing and can induce anti-tumor immunity (eg, Leach et al., Science 271). Kron et al., Proc. Natl. Acad. Sci. USA 94: 8099-8103 (1997); Kwon et al., Natl. Acad. Sci. USA 96: 15074-15079 (1999). Yang et al., Cancer Res 57: 4036-41 (1997); see Hurwitz et al., Proc. Natl. Acad. Sci. USA 95: 10067-71 (1998)). CTLA4 antibodies and their uses are described, for example, in the following applications and patents: US patent application 09 / 472,087, now published as US Pat. No. 6,682,736; International application PCT / US99 / 30895 (published as WO 00/37504 on June 29, 2000); US patent application No. 10 / 612,497 (published as US patent application publication No. 2004/0228858 on November 18, 2004); US patent application No. 10 / 776,649 (published on Nov. 18, 2004 as US Patent Application Publication No. 2004/0228861); International Application PCT / US00 / 23356 (published on Mar. 1, 2001 as WO 01/14424) ( For example, Medarex, MDX-010 in Princeton, New Jersey, And also known as ipilimumab 10D1); international application PCT / US99 / 28739 (published as WO 00/32231 on June 8, 2000); US Pat. Nos. 5,811,097, 5,855,887, 6,051,227 and 6,207,156; Linsley et al., US Pat. No. 5,844,095; International Application PCT / US92 / 05202 (published on Jan. 7, 1993 as WO 93/00431) U.S. Patent Application No. 10 / 153,382 (published May 8, 2003 as U.S. Patent Application Publication No. 2003/0086930); U.S. Patent Application No. 10 / 673,738 (U.S. Patent Application Publication No. 2005 / Published on Feb. 24, 2005 as 0042223); US patent application Ser. No. 11 / 085,368 (US Published on Oct. 13, 2005 as Patent Application Publication No. 2005/0226875); U.S. Patent Application No. 60 / 624,856 (filed on Nov. 4, 2004), now as WO 2006/048749 on May 11, 2006 Published in U.S. Patent Application No. 60 / 664,364 (filed on Mar. 23, 2005) and U.S. Patent Application No. 60 / 711,707 (filed on Aug. 26, 2005), now WO 2006/101691 Published on Sep. 28; U.S. Patent Application No. 60 / 664,653 (filed on Mar. 23, 2005), now published on Sep. 28, 2006 as WO 2006/101692; U.S. Patent Application No. 60 / 697,082. Issue (filed on July 7, 2005), now published on January 18, 2007 as WO 2007/008463.

  Despite the success of currently available anti-cancer therapies, complete responses to these treatments or prolonged survival are rarely observed, and the patient population refractory to these treatments remains large. Thus, there is a need to develop new therapies, particularly those that can increase or enhance the antitumor activity of other antitumor agents while reducing the cytotoxic side effects of current chemotherapeutic drugs. Although not done, the present invention satisfies this need.

The invention includes a method of cancer treatment in a patient in need of cancer treatment. The method is used in combination with a therapeutically effective amount of at least one therapeutic agent, such as a therapeutically effective amount of an anti-CTLA4 antibody, such as ipilimumab (also referred to as MDX-010) and CP-675,206 (11.2.1. And also called ticilimumab) to the patient, the cancer and the agent are
(A) when the cancer is non-Hodgkin lymphoma (NHL) and the agent is rituximab;
(B) when the cancer is NHL and the agent is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP);
(C) when the cancer is NHL and the agent is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R);
(D) when the cancer is lung cancer and the agent is bevacizumab;
(E) the cancer is non-small cell lung cancer (NSCLC) and the agent is gefitinib;
(F) the cancer is NSCLC and the agent is bevacizumab;
(G) the cancer is NSCLC, the agent is a taxane and gemcitabine, and the taxane is selected from the group consisting of docetaxel and paclitaxel;
(H) when the cancer is NSCLC and the agent is a taxane and a platinum compound;
(I) when the cancer is NSCLC and the agent is docetaxel;
(J) when the cancer is NSCLC and the agent is erlotinib;
(K) when the cancer is NSCLC and the agent is pemetrexed;
(L) When the cancer is NSCLC and the agent is a platinum compound;
(M) the cancer is gastric cancer and the agent is irinotecan;
(N) the cancer is gastric cancer and the agent is fluorouracil and leucovorin;
(O) the cancer is liver cancer and the agents are doxorubicin, ifosfamide and vincristine;
(P) the cancer is liver cancer and the agents are doxorubicin and vincristine;
(Q) the cancer is colorectal cancer (CRC) and the agent is fluorouracil;
(R) the cancer is CRC and the agent is capecitabine;
(S) when the cancer is CRC and the agents are fluorouracil, leucovorin and oxaliplatin (FOLFOX);
(T) when the cancer is CRC and the agents are fluorouracil, leucovorin and irinotecan (FOLFIRI);
(U) the cancer is CRC and the agent is cetuximab;
(V) the cancer is chronic myelogenous leukemia (CML) and the agent is imatinib mesylate;
(W) the cancer is chronic lymphocytic leukemia (CLL) and the agent is imatinib mesylate;
(X) the cancer is pancreatic cancer and the agent is gemcitabine;
(Y) when the cancer is breast cancer and the agent is a taxane;
(Z) when the cancer is breast cancer and the agent is cyclophosphamide, doxorubicin and taxane;
(Aa) the cancer is breast cancer and the agent is selected from the group consisting of tamoxifen, anastrazol, letrozole, and fulvestrant;
(Bb) when the cancer is breast cancer and the agent is trastuzumab;
(Cc) when the cancer is breast cancer and the agent is bevacizumab;
(Dd) when the cancer is breast cancer and the agent is cetuximab;
(Ee) when the cancer is breast cancer and the agent is axitinib;
(Ff) the cancer is bladder cancer and the agent is bacilli Calmette Guerin (BCG);
(Gg) when the cancer is bladder cancer and the agents are gemcitabine and cisplatin;
(Hh) when the cancer is melanoma and the agent is interferon alpha;
(Ii) the cancer is multiple myeloma and the agent is bortezomib;
(Jj) selected from the group consisting of when 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.

  In one aspect, the treatment is selected from the group consisting of neoadjuvant therapy, adjuvant therapy, first line therapy, second line therapy, and third line therapy.

  In other embodiments, the agent is administered sequentially or concurrently with the antibody.

  In yet another aspect, the taxane is paclitaxel and the platinum compound is carboplatin.

  In one aspect, 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, and the treatment comprises a second line therapy.

  In one aspect, the therapeutically effective amount of the antibody is about 1 mg / kg to 40 mg / kg.

  In other embodiments, the therapeutically effective amount of the antibody is about 3 mg / kg to 15 mg / kg.

  In one aspect, the NHL is low grade NHL and the treatment comprises first line therapy.

  In other embodiments, the NHL is high grade NHL and the treatment comprises second line therapy.

  In a further aspect, the treatment comprises first line therapy.

  In one aspect, the cancer is CRC, the agent is capecitabine, and the treatment comprises first line therapy.

  In another aspect, the cancer is CRC, the agent is FOLFOX, and the treatment is selected from the group consisting of first line therapy and adjuvant therapy after surgical resection of the primary colon tumor.

  In one aspect, the cancer is CML, the agent is imatinib mesylate, and the treatment comprises first line therapy.

  In other embodiments, the cancer is CLL, the agent is imatinib mesylate, and the treatment comprises first line therapy.

  In a further aspect, the cancer is pancreatic cancer, the agent is gemcitabine, the pancreatic cancer is selected from the group consisting of unresectable stage II, locally advanced stage III, and metastatic stage IV, and the treatment is first Includes selective therapy.

  In other embodiments, the cancer is breast cancer, the agent is a taxane, and the treatment comprises first line therapy.

  In one aspect, the cancer is ovarian cancer, the agents are carboplatin and paclitaxel, and the treatment comprises first line therapy.

  The invention includes a kit for treating NSCLC comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of carboplatin; a therapeutically effective amount of paclitaxel; an applicator; and instructions for using the kit.

  In one aspect, the kit further comprises a therapeutically effective amount of at least one agent selected from the group consisting of bevacizumab, sunitinib, and PF03512676.

  The present invention relates to 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 instructions for using the kit for NSCLC treatment Includes kit.

  The invention includes a kit for CRC treatment comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of carboplatin; a therapeutically effective amount of paclitaxel; an applicator; and instructions for using the kit.

  The present invention relates to a therapeutically effective amount of CP-675,206; a therapeutically effective amount of fluorouracil; a therapeutically effective amount of leucovorin; a therapeutically effective amount of oxaliplatin; an applicator; and instructions for using the kit. Includes kit.

  The invention includes a kit for treating pancreatic cancer comprising a therapeutically effective amount of CP-675,206; a therapeutically effective amount of gemcitabine; an applicator; and instructions for using 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 instructions for using the kit.

  The present invention includes methods for preventing or treating HIV infection or preventing, treating or delaying the development of AIDS in a patient in need thereof. The method comprises administering to a patient a therapeutically effective amount of an anti-CTLA4 antibody CP-675,206, comprising an HIV protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, a nucleoside / nucleotide reverse transcriptase inhibitor, a CCR5 antagonist, At least one therapeutically effective amount selected from the group consisting of an inhibitor of the interaction of CD4 and gp120, an HIV fusion inhibitor, an HIV integrase inhibitor, an RNase H inhibitor, a prenylation inhibitor, and a maturation inhibitor The method further includes administering an antiviral agent.

  In one aspect, the CCR5 antagonist is maraviroc.

  In another aspect, the method further comprises assessing HIV co-receptor tropism.

  The present invention includes a method of preventing or treating HIV infection or preventing, treating or delaying the onset of AIDS in a patient in need thereof, comprising a therapeutically effective amount of an anti-CTLA4 antibody and A method of administering maraviroc to a patient.

  In one aspect, the anti-CTLA4 antibody is selected from the fraction consisting of CP-675,206 and ipilimumab.

  Alternative embodiments of the invention are described below, including those that use alternative anti-CTLA4 antibodies and involve different methods.

  The foregoing summary, as well as the following detailed description of the present invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. However, it should be understood that the invention is not limited to the precise procedures and instrumentalities shown.

  Unless defined otherwise herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In general, the nomenclature used for cell culture, tissue culture, molecular biology, immunology, microbiology, genetics, protein chemistry and nucleic acid chemistry, techniques thereof, and the hybridizations described herein are well known in the art. And are usually used.

  The methods and techniques of the present invention are generally described in various general and more specific references cited and discussed throughout this specification, according to methods well known in the art, unless otherwise indicated. Implement as follows. Such references include, for example, Sambrook and Russell, “Molecular Cloning, A Laboratory Approach”, Cold Spring Harbor Press, Cold Spring Harbor, NY (2001), Ausubel, which is incorporated herein by reference. “Current Protocols in Molecular Biology”, John Wiley & Sons, New York State (2002), and Harlow and Lane, “Antibodies: A Laboratory Harbor New York, Cold Spring Harbor State, New York, New York” rbor (1990). Enzymatic reactions and purification techniques are performed according to the manufacturer's specifications, as is routinely performed in the art or as described herein. The nomenclature used in connection with analytical chemistry, synthetic organic chemistry, medicinal chemistry and pharmaceutical chemistry described herein and its experimental procedures and techniques are well known and commonly used in the art. Standard techniques are used for chemical synthesis, chemical analysis, formulation, formulation, and delivery, and patient treatment.

  As used herein, each of the following terms has the meaning associated with it in this section.

  The articles “a” and “an” are used herein to refer to one or more (ie, at least one) of the grammatical objects of the article. By way of example, “an element” means one element or a plurality of elements.

  In this specification, 20 conventional amino acids and their abbreviations follow conventional usage. See "Immunology--A Synthesis" (2nd edition, edited by ES Golub and DR Gren, Sinauer Associates, Sunderland, Mass., 1991), incorporated herein by reference.

  A “conservative amino acid substitution” is one in which the amino acid residue is replaced with another amino acid residue having a side chain R group with similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions do not substantially change the functional properties of the protein. If two or more amino acid sequences differ from each other by conservative substitutions, the degree of% sequence identity or similarity can be adjusted upwards to correct the conservative nature of the substitution. Means for making this adjustment are well known to those skilled in the art. Pearson, Methods Mol. Biol. 243: 307-31 (1994).

  Examples of groups of amino acids having 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; 7) Sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, leucine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine.

  Alternatively, a conservative substitution is any change that results in a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256: 1443-45 (1992). A “moderately conservative” replacement is any change that results in a non-negative value in the PAM250 log-likelihood matrix.

  Preferred amino acid substitutions (1) reduce the sensitivity of such analogs to (1) proteolysis, (2) reduce the sensitivity to oxidation, (3) alter the binding affinity of protein complex formation, (4) It imparts or modifies other physicochemical or functional properties. Analogs containing substitutions, deletions, and / or insertions can include various muteins of sequences other than the specific peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) in a particular sequence (preferably part of a polypeptide outside the domain (s) that form intermolecular contacts, eg outside the CDRs) )It can be performed. With conservative amino acid substitutions, the structural characteristics of the parent sequence should not substantially change (e.g., a substituted amino acid breaks the helical structure present in the parent sequence or alters other types of secondary structures that characterize the parent sequence). Should not tend to destroy). Examples of secondary and tertiary structures of art-recognized polypeptides are “Proteins, Structures and Molecular Principles” (Creighton, Ed., WH Freeman), each of which is incorporated herein by reference. and Company, New York (1984)); “Introduction to Protein Structure” (edited by C. Branden and J. Tokyo, Garland Publishing, New York, NY (1991)); and Thornton et al., Nature 354: 1991: 354: 105. Has been.

  Polypeptide sequence similarity is usually 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. For example, the Genetics Computer Group (also known as Wisconsin Package) (GCG available from Genetics Computer Group, Inc.) is an integrated software package consisting of over 130 programs that access, analyze and manipulate nucleotide and protein sequences. is there. GCG includes programs such as “Gap” and “Bestfit” and uses them with default parameters to make use of between closely related polypeptides, such as homologous polypeptides from different species of organisms, or wild type Sequence similarity, homology and / or sequence identity can be determined between the protein and its mutant protein. See, for example, GCG Version 6.1, Version 7.0, Version 9.1, and Version 10.0.

  Polypeptide sequences can also be compared using the program FASTA in GCG using default or recommended parameters. FASTA (eg, FASTA2 and FASTA3) provides the best overlap region alignment and% sequence identity between the query and search sequences (Pearson, Methods Enzymol. 183: 63-98 (1990); Pearson, Methods) Mol.Biol.132: 185-219 (2000)). Another preferred algorithm for comparing a sequence of the invention with a database containing a large number of sequences from different organisms is the computer program BLAST, in particular blastp or tblastn, using default parameters. See, for example, Altschul et al., J. MoI. Mol. Biol. 215: 403-410 (1990); Altschul et al., Nucleic Acids Res. 25: 3389-402 (1997).

A complete “antibody” comprises at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. See generally, “Fundamental Immunology”, Chapter 7 (Paul, W. Ed., 2nd edition, Raven Press, NY (1989)), which is 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. The _VH and _VL regions can be further divided into hypervariable regions called complementarity determining regions (CDRs) interspersed with conserved regions rather than framework regions (FR). _VH and _VL are each composed of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The amino acid assignments for each domain are as follows: Kabat, “Sequences of Proteins of Immunological Interest” (National Institutes of Health, Bethesda, MD (1987 and 1991)), or Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987); Chothia et al., Nature 342: 878-883 (1989).

The term “antigen-binding portion” (or simply “antibody portion”) of an antibody refers herein to one or more fragments of an antibody that retain the ability to specifically bind an antigen (eg, CTLA4). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include: (i) a monovalent fragment consisting of the V _L , V _H , C _L and C _H 1 domains, referred to as a Fab fragment; ii) a F (ab ′) ₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of V _H and C _H 1 domains; (iv) an antibody An Fv fragment consisting of the _VL and _VH domains of a single arm of (v) a dAb fragment consisting of the _VH domain (Ward et al. (1989) Nature 341: 544-546); and (vi) isolation Complementarity determining regions (CDRs). Furthermore, although the two domains V _L and V _H of the Fv fragment are encoded by separate genes, they are recombined using a monovalent molecule paired with the V _L and V _H regions. Can be joined by synthetic linkers that allow them to be made as single protein chains (known as single chain Fv (scFv)) that form: Bird et al., Science 242: 423-426. (1988) and Huston et al., Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. Other types of single chain antibodies such as bispecific antibodies are also encompassed. Bispecific antibodies are bivalent, bispecific antibodies, where the V _H and V _L domains are expressed on a single polypeptide chain, but are too short between two domains on the same chain. A linker that cannot be paired is used, whereby the domain pairs with the complementary domain of the other chain and two antigen binding sites are generated (see, eg, Holliger et al., Proc. Natl. Acad. Sci.USA 90: 6444-6448 (1993); see Poljak et al., Structure 2: 1121-1123 (1994)).

Furthermore, the antibody or antigen binding portion thereof may be part of a large immunoadhesion molecule formed by covalent or non-covalent attachment of the antibody or antibody portion and one or more other proteins or peptides. Examples of such immunoadhesion molecules include the use of the streptavidin core region to create tetrameric scFv molecules (Kipriyanov et al., Human Antibodies and Hybridomas 6: 93-101 (1995)), and bivalent and biotinylated There is the use of cysteine residues, marker peptides and a C-terminal polyhistidine tag (Kipriyanov et al., Mol. Immunol. 31: 1047-1058 (1994)) to make scFv molecules. In another example, one or more CDRs from an antibody are covalently or non-covalently incorporated into a molecule to make it an immunoadhesive factor that specifically binds to an antigen of interest such as CTLA4. There is. In such embodiments, the CDR (s) can be incorporated as part of a larger polypeptide chain, can be covalently linked to other polypeptide chains, or can be incorporated non-covalently. it can. Antibody parts such as Fab and F (ab ′) ₂ fragments can be prepared from the whole antibody using conventional techniques such as papain digestion and pepsin digestion of the whole antibody. Furthermore, as described herein, standard recombinant DNA techniques can be used to obtain antibodies, antibody portions and immunoadhesion molecules.

It should be understood that when referring to an “antibody” herein with respect to the present invention, the antigen binding portion thereof can also be used. The antigen binding moiety competes with the complete antibody for specific binding. See generally, Fundamental Immunology, Chapter 7 (Paul, W. Ed., 2nd Edition, Raven Press, NY (1989)), which is incorporated by reference in its entirety for all purposes. Antigen-binding portions can be made by recombinant DNA techniques or by enzymatic or chemical cleavage of complete antibodies. In some embodiments, the antigen-binding portions, Fab, Fab ', F ( ab') 2, Fd, Fv, dAb, complementarity determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies, There are bispecific antibodies and polypeptides comprising at least a portion of an antibody sufficient to confer specific antigen binding to the polypeptide. In embodiments having one or more binding sites, the binding sites may be the same or different from one another.

  The terms “human antibody” or “human sequence antibody” are used interchangeably herein and include antibodies having variable and constant regions (if present) derived from human germline immunoglobulin sequences. . Human sequence antibodies of the present invention may comprise amino acid residues that are not encoded by human germline immunoglobulin sequences (eg, random or site-directed mutagenesis in vitro, or somatic mutation in vivo). Mutation introduced by). However, as used herein, the term “human antibody” refers to a “chimeric” antibody (ie, “humanized” or “human antibody”) in which CDR sequences derived from the germline of other mammalian species such as mice are grafted onto a human framework sequence. PRIMATIZED ™ antibody).

  As used herein, the term “chimeric antibody” refers to an antibody that comprises regions from two or more different antibodies. In one embodiment, the one or more CDRs are derived from a human anti-CTLA4 antibody. In other embodiments, the CDRs are all derived from human anti-CTLA4 antibodies. In other embodiments, CDRs from multiple human anti-CTLA4 antibodies are mixed in a chimeric human antibody. For example, the chimeric antibody is derived from the CDR1 derived from the light chain of the first human anti-CD40 antibody, the CDR2 derived from the light chain of the second human anti-CTLA4 antibody, and the light chain of the third human anti-CTLA4 antibody. CDR3 may be included and the heavy chain CDRs may be derived from one or more other anti-CD40 antibodies. Further, the framework region may be derived from one of the same anti-CTLA4 antibodies, or may be derived from one or more different (multiple) humans.

  Furthermore, as discussed hereinabove, chimeric antibodies include antibodies that comprise portions derived from germline sequences of multiple species.

  “Glycoform” refers to a complex sugar chain structure containing linkages of various carbohydrate units. Such a structure is described, for example, in “Essentials of Glycobiology” reviewed by standard glycobiology nomenclature, edited by Varki et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1999). Are listed. Such glycoforms include, but are not limited to, G2, G1, G0, G-1, and G-2 (see, eg, International Patent Application WO99 / 22764).

  A “glycosylation pattern” is a pattern of carbohydrate units that are covalently linked to a protein (eg, glycoform), as well as the glycoform (s) covalently linked to the peptide backbone of the protein, and more specifically to an immunoglobulin protein ( Defined as a pattern of carbohydrate units that are covalently bound to the site (s).

  Antibodies expressed by different cell lines or in transgenic animals are likely to have different glycoforms and / or glycosylation patterns compared to each other. However, any antibody encoded by a nucleic acid molecule provided herein or comprising an amino acid sequence provided herein is part of the invention, regardless of antibody glycosylation.

  As used herein, the term “effective amount” or “therapeutically effective amount” when administered to a mammal, preferably a human, results in a detectable therapeutic response compared to the response detected in the absence of the compound. Means quantity. A therapeutic response such as, but not limited to, inhibition and / or reduction of tumor growth, tumor size, metastasis, etc. is recognized in many of the art, including, for example, the methods disclosed herein. It can be easily evaluated by the method.

  The skilled artisan will vary in the effective amount of the compound or composition administered herein, 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 It will be appreciated that it can be readily determined based on several factors such as the particular compound being administered.

  With respect to an antibody, the term “competing” herein means that the first antibody, or antigen binding portion thereof, competes with the second antibody, or antigen binding portion thereof, for binding, The binding of the antibody to its cognate epitope is detectably reduced in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. An alternative case where the binding of the second antibody and its epitope is also detectable to the extent that it is present in the presence of the first antibody is applicable, but need not be. That is, the first antibody can inhibit the binding between the second antibody and its epitope even if the second antibody does not inhibit the binding between the first antibody and its respective epitope. However, if each antibody inhibits the binding of another antibody and its cognate epitope or ligand to a detectable extent, whether it is the same, greater or lesser, then that antibody will It can be said that they are "cross-competing" with each other in the epitope binding. For example, a cross-competing antibody can bind to the epitope, or part of the epitope, to which the antibody used in the invention binds. The use of both competing and cross-competing antibodies is encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (eg, steric hindrance, structural change, or binding to a common epitope or portion thereof), one of ordinary skill in the art will be based on the teachings provided herein. Thus, it will be appreciated that such competing or cross-competing antibodies are encompassed and may be useful in the methods disclosed herein.

  The term “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 and sugar side chains and usually have specific three-dimensional structural characteristics as well as specific charge characteristics. Structural epitopes and nonstructural epitopes are distinguished by the loss of binding to the former but not the latter in the presence of a denaturing solvent.

  “Instructions”, as that term is used herein, includes publications, records, figures, or any other expressive medium, which may be used to refer to the various listed herein. The usefulness of the compounds, combinations, and / or compositions of the invention in kits for altering, alleviating or treating various diseases or disorders can be communicated. Optionally, or in the instructions, describe one or more methods for alleviating a disease or disorder in a cell, tissue, or mammal, including those disclosed elsewhere herein. You can also.

  The instructions for the kit can be attached, for example, to a container containing the compound and / or composition of the invention, or can be shipped with a container containing the compound and / or composition. Alternatively, the instructions can be shipped separately from the container with the intention that the recipient uses the instructions and the compound together.

  Except where noted, the terms “patient” or “subject” are used interchangeably and include mammals such as human patients and non-human primates, and veterinary subjects such as rabbits, rats, mice and other animals. Point to. Preferably, the patient refers to a human.

  In this specification, polypeptide sequences are expressed using conventional notation. The left end of the polypeptide sequence is the amino terminus and the right end of the polypeptide sequence is the carboxyl terminus.

The phrase “specifically binds” is used herein to refer to a compound that recognizes and binds to a specific molecule, but does not substantially recognize or bind to other molecules in the sample, such as a protein, Means nucleic acid, antibody, and the like. For example, an antibody or peptide inhibitor that recognizes and binds to a cognate ligand in a sample but does not substantially recognize or bind to other molecules in the sample (eg, binds to its cognate antigen CTLA4) Anti-CTLA4 antibody). Thus, under the indicated assay conditions, a specific binding moiety (eg, an antibody or antigen-binding portion thereof) binds preferentially to a specific target molecule and is significant from other components present in the test sample. Do not combine by quantity. A variety of assay formats can be used to select antibodies that specifically bind to the molecule of interest. Among the numerous assays that can be used to identify antibodies that specifically react with CTLA4 are, for example, solid phase ELISA immunoassays, immunoprecipitation, BIAcore, FACS, and Western blot analysis. Typically, a specific or selective reaction is at least twice background signal or noise, more typically more than 10 times background, and more specifically antibodies Can be said to “specifically bind” to an antigen when the equilibrium dissociation constant (K _D ) is ≦ 1 μM, preferably ≦ 100 nM, and most preferably ≦ 10 nM.

The term “K _D ” refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

  As used herein, “substantially pure” means that the subject species is the predominant species present (ie, it is more abundant than any other individual species in the composition on a molar basis). ), Preferably the substantially purified fraction means that the composition comprises at least about 50% of the subject species (eg, anti-CTLA4 antibody) of all macromolecular species present. In general, a substantially pure composition will comprise greater than about 80% of the total macromolecular species present in the composition, more preferably greater than about 85%, 90%, 95%, and 99%. Most preferably, the subject species is purified until it is essentially homogeneous (contaminant species cannot be detected in the composition by conventional detection methods), and the composition is essentially from a single macromolecular species. Become.

  As used herein, “treating” refers to the frequency with which a patient experiences symptoms of a disease (ie, tumor growth and / or metastasis, or other effects mediated by the number and / or activity of immune cells). Means to reduce. The term includes administration of a compound or agent of the invention to prevent or delay the onset of symptoms, complications, or biochemical signs of disease, alleviate symptoms, or disease, condition, or It includes stopping or inhibiting further development of the disorder. Treatment may be prophylactic (preventing or delaying the onset of the disease, or preventing its clinical or subclinical manifestations), or therapeutic suppression or relief of symptoms after the onset of the disease. But you can.

  “Combination therapy” encompasses the administration of immunostimulatory anti-CTLA4 antibodies, preferably CP-675,206, and other therapeutic agents that are part of a particular therapy that may include a maintenance phase, these It is intended to produce beneficial effects from the interaction of other therapeutic agents. The beneficial effects of a combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of therapeutic agents. Co-administration of these therapeutic agents is usually performed over a defined period of time (usually minutes, hours, days or weeks depending on the combination selected). “Combination therapy” is generally not intended to include the administration of two or more of these therapeutic agents that are part of separate single therapies that have been accidentally and optionally combined in the present invention.

  “Combination therapy” refers to the sequential administration of these therapeutic agents, ie, the administration of each therapeutic agent at different times, as well as the therapeutic agents, or at least two therapeutic agents substantially simultaneously. Includes administration. Sequential or substantially simultaneous administration of each therapeutic agent is any suitable route including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue. Can be implemented. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent (eg, a chemotherapeutic agent) can be administered orally, and a second agent (eg, an anti-CTLA4 antibody) can be administered intravenously. Furthermore, the selected combination of the first therapeutic agents may be administered by intravenous injection, while the second therapeutic agent of the combination may be administered orally. Alternatively, both therapeutic agents may be administered, for example, by intravenous or subcutaneous injection.

  As used herein, the term “sequential” means that unless otherwise specified, is characterized by a regular order or order, eg, administration includes administration of an anti-CTLA4 antibody and a chemotherapeutic agent. In some cases, sequential administration methods may include administration of the anti-CTLA4 antibody prior to, substantially simultaneously with, or subsequent to administration of the chemotherapeutic agent, although both agents are administered in a regular order or sequence. The The term “separate” means that one is separated from the other, unless otherwise specified. The term “simultaneously” means unless otherwise specified, that occurs or occurs at the same time, that is, the compounds of the invention are administered at the same time. The term “substantially simultaneously” means that the compounds are administered within a few minutes of each other (eg, within 10 minutes of each other) and are meant to include co-administration as well as sequential administration, In some cases, it is only a short time away (eg, the time it takes for the physician to administer the two compounds separately). As used herein, simultaneous administration and substantially simultaneous administration are used interchangeably. Sequential administration refers to time-separated administration of anti-CTLA4 antibody and chemotherapeutic agent.

  “Combination therapy” also includes other biologically active ingredients (such as, but not limited to, second different antitumor agents, such as dendritic cell vaccines and other tumor vaccines) and non-drug therapies (including but not limited to Administration of a therapeutic agent as described above in a further combination with surgery or radiation therapy) may also be included. Where the combination therapy further includes radiation therapy, the radiation therapy can be performed at any suitable time as long as a beneficial effect is realized from the combined interaction of the therapeutic agent and the radiation therapy. For example, where appropriate, beneficial effects are still achieved even when the therapeutic agent administration and radiation therapy are separated in time, perhaps days or weeks.

  As used herein, the term “adjuvant therapy” refers to treatment that follows a primary treatment, including but not limited to radiation, chemotherapy, hormone therapy, and the like. The goal of adjuvant therapy is to increase the patient's chances of remission or cure, increase the patient's overall survival benefit, and help reduce the risk of recurrence. Thus, when a combination of an anti-CTLA4 antibody and a therapeutic agent is administered as an adjuvant therapy, the combination can be administered after the primary therapy, eg, subjecting the patient to surgery, radiation and / or chemotherapy treatment. It will then be understood that a course of treatment of the combination of anti-CTLA4 antibody and therapeutic agent will be conducted. In this regard, the dosage of anti-CTLA4 antibody and therapeutic agent can be considered a therapeutic or maintenance dose, depending on the goal of adjuvant therapy. The term “neoadjuvant therapy” refers to treatment performed prior to primary treatment, including but not limited to surgery, radiation, chemotherapy, and the like. When setting a neoadjuvant, the dose of anti-CTLA4 antibody and therapeutic agent is considered a therapeutic dose.

  The term “first line therapy” refers to a first type of therapy that is performed for a condition or disease, or a first therapy that is selected for the treatment of a particular type of cancer. Therefore, the term “second-line therapy” always refers to treatment given when the first or first-line therapy is unsuccessful, and “third-line therapy” refers to both the first and subsequent treatments. Refers to a treatment or treatment that is performed when unsuccessful.

1. Combination therapy A. Cancer A variety of cancers can be treated using the CTLA4 antibodies described herein. Without being bound by a particular theory, administration of a therapeutic agent can produce a synergistic effect when administered with an immunopotentiating anti-CTLA4 antibody. Without being bound by any particular theory, agents that mediate anti-tumor effects can mediate tumor burden reduction and mediate tumor antigen increase in the host antigen-presentation pathway. Inflammation can be reduced so that antibodies and / or other therapeutic agents can better penetrate the tumor and / or can mediate the reduction of immunosuppressive tumor factors. Thus, the combination of anti-CTLA4 antibody and at least one therapeutic agent can mediate a synergistic therapeutic effect, thereby providing greater benefit to either patient in need of either compound alone.

  Cancers that can be treated include, but are not limited to, human sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, Kaposi sarcoma, chordoma, angiosarcoma, endothelial sarcoma Lymphangiosarcoma, lymphatic endothelial sarcoma, synovial, mesothelioma, erythroblastoma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, primary or secondary brain tumor, colon carcinoma, pancreatic cancer, breast cancer, ovary Cancer, uterine cancer, cervical cancer, prostate cancer, skin cancer, bone cancer, small intestine cancer, anal area cancer, head and neck cancer, gastrointestinal (stomach, colorectal, and duodenum) cancer, esophageal cancer, squamous cell carcinoma, basal Centers including cell carcinoma, adenocarcinoma, sweat gland carcinoma, cutaneous or intraocular melanoma, endometrial cancer, vaginal cancer, fallopian tube cancer, vulvar cancer, cervical cancer, primary or secondary CNS tumors Nervous system (CNS) tumor, spinal axis tumor, primary CNS lymphoma, brain stem god Glioma, pituitary adenoma, sebaceous cancer, papillary cancer, papillary adenocarcinoma, cystadenocarcinoma, medullary cancer, bronchogenic cancer, gastric cancer, colon cancer, rectal cancer, renal cell carcinoma (RCC), hepatocellular carcinoma, Cholangiocarcinoma, gallbladder cancer, liver cancer, renal cancer, gastroesophageal cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, testicular tumor, penile cancer, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) ), Thyroid cancer, parathyroid cancer, carcinoid tumor, urethral cancer, ureteral cancer, renal pelvic cancer, endocrine cancer, adrenal cancer, pancreatic endocrine tumor (pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor ), Bladder cancer, epithelial carcinoma, glioma, astrocytoma, pituitary adenoma, corticocarcinoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangiomas (angioma, Including benign and malignant tumors such as hemangiosarcoma, hemangioblastoma and lobular capillary hemangioma) Acoustic neuroma, oligodendroglioma, meningioma, melanoma, cholangiocarcinoma, neuroblastoma, retinoblastoma, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, myeloblastic leukemia, promyelocytic leukemia, Myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic leukemia, lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelocytic leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia, lymphocytic Lymphoma, polycythemia vera, lymphoma, Hodgkin's disease lymphoma, non-Hodgkin's disease lymphoma, cutaneous T-cell lymphoma (CTCL), cutaneous B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, soft part There are tissue sarcomas, gastrointestinal stromal tumors (GIST), glioblastomas, or a combination of one or more of the above cancers.

  In preferred embodiments, the cancer includes non-Hodgkin lymphoma, non-small cell lung cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, pancreatic cancer, breast cancer and ovarian cancer.

  Although various preferred combination therapies are described herein for various cancers, in particular embodiments described herein, the invention is not limited to these or any other combination therapies .

1. Non-Hodgkin lymphoma (NHL)
In one embodiment, the present invention comprises administration of CP-675,206 for NHL treatment in combination with at least one therapeutic agent, preferably rituximab (RITUXAN; Genentech, San Francisco, Calif.).

  The combination can be administered to treat patients with low grade NHL or high grade NHL. In one embodiment, the NHL is a low grade NHL and a combination of CP-675,206 and rituximab is the first line therapy. In a further embodiment, after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and / or CHOP-R (cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab), the combination therapy as a second line therapy Do. In a further embodiment, rituximab is administered as a single agent (SA) therapy after the combination. The combination of rituximab and CP-675,206 can increase and / or prolong the anti-tumor cell response, thereby providing a therapeutic benefit to patients suffering from NHL.

  In one embodiment, a combination of CP-675,206 and rituximab is administered as a second line therapy to treat high grade NHL refractory to CHOP-R. In other embodiments, if the treatment is a second line therapy for high grade NHL refractory to CHOP-R, the method further comprises administering rituximab after administering the CP-675,206 / rituximab combination. Administering as a monotherapy.

  In other embodiments, a combination of CP-675,206 and rituximab is administered to the patient as a second line therapy after other treatments including but not limited to chemotherapy or bone marrow transplantation. In one aspect, a combination of CP-675,206, rituximab is administered after bone marrow depletion chemotherapy and bone marrow transplantation (BMT). In other embodiments, the combination is administered as a first line therapy followed by bone marrow depletion chemotherapy and BMT. A method well known in the art for evaluating treatment strategies for NHL treatment, taking into account various known factors such as patient age and condition, disease stage, etc., is a combination therapy that helps patients with high-grade NHL It can be used to make decisions when suggested to be treated.

2. Non-small cell lung cancer (NSCLC)
In one embodiment, the invention includes a method of treating NSCLC, the method comprising administering a combination comprising CP-675,206 and a therapeutic agent to a patient in need of treatment. In one aspect, the agent is a non-immunosuppressive chemotherapeutic agent such as, but not limited to, gefitinib (IRESSA). The combination of CP-675,206 and a therapeutic agent can increase the immune response against the tumor, due in particular to increased release of tumor antigen with the cytotoxic effect of the chemotherapeutic agent. Thus, one of skill in the art, based on the disclosure provided herein, can use any therapeutic agent that mediates cell death and / or release of tumor antigens with an anti-CTLA4 antibody to generate an immune response against the tumor. It will be appreciated that it can be increased, thereby providing a therapeutic benefit to the patient. Moreover, those skilled in the art will further understand that, after having learned the teachings provided herein, the therapeutic effect can be further enhanced and the therapeutic agent does not reduce the immune enhancing effect of the antibody. Let's go. Although gefitinib is a chemotherapeutic agent that is known not to reduce a patient's immune response, the invention is not limited to this or any other specific therapeutic agent. Rather, in one embodiment, the invention encompasses the administration of CP-675,206, and therapeutic agents that can mediate a therapeutic response against NSCLC tumors.

  In one embodiment of the invention, the treatment comprises performing a combination therapy including CP-675,206, and platinum-based chemotherapy. In one aspect, CP-675,206 is administered to NSCLC patients after a course of platinum-based therapy as adjuvant therapy. That is, CP-675,206 is administered to patients who have received a course of platinum-based therapy and who have responded or remain stable. In one aspect, the patient's NSCLC is a stage IIIb (with leaching) or stage IV disease that responds or remains stable after approximately 6 platinum-containing treatments. In a further aspect, the patient is administered CP-675,206 at least about 3 weeks after the last platinum-based chemotherapy. In yet another embodiment, CP-675,206 is administered within about 6 weeks after the last platinum-based chemotherapy. In other embodiments, CP-675,206 is administered at least about 3 weeks after the last platinum-based chemotherapy but within 6 weeks. In one aspect of the invention, platinum-based chemotherapy includes cisplatin, carboplatin, eptaplatin, donkeyplatin, nedaplatin, oxaliplatin (ELOXATIN, Sanofi), streptozocin, satraplatin (JM-126), etc. Includes platinum-based compounds selected from compounds.

  In another embodiment of the invention, the treatment of lung cancer comprises administration of bevacizumab (AVASTIN) and CP-675,206. In one aspect, lung cancer includes non-small cell lung cancer and small cell lung cancer. In other embodiments, the lung cancer comprises small cell lung cancer.

  In other embodiments, the cancer is NSCLC and the treatment includes administration of CP-675,206 in combination with a taxane, which includes, but is not limited to, docetaxel (TAXOTERE), and paclitaxel (TAXOL). Often combined with gemcitabine (GEMZAR).

  In a further aspect of the invention, the invention encompasses a method of treating NSCLC, the method comprising administration of CP-675,206, taxanes (eg, docetaxel and paclitaxel), and platinum compounds. In one aspect, the method of treating NSCLC is a first line therapy comprising administering a combination of CP-675,206, taxane and a platinum compound, wherein the taxane is paclitaxel and platin is carboplatin (carbo / Paclitaxel). In other embodiments, the combination of CP-675,206, paclitaxel and carboplatin is administered simultaneously or sequentially. In a further aspect, the paclitaxel / carboplatin combination is administered before or after administration of CP-675,206. That is, the antibody is administered simultaneously in combination with carbo / paclitaxel therapy, or it is administered after carbo / paclitaxel therapy. The interval between performing carbo / paclitaxel therapy and administering the antibody can be readily determined by one skilled in the art based on well-known methods. In one aspect, the cancer is locally advanced stage IIIb NSCLC. In another aspect, the NSCLC is metastatic stage IV NSCLC. In other embodiments, the CP-675,206-carboplatin-paclitaxel combination is administered with bevacizumab. In another aspect, the CP-675,206-carboplatin-paclitaxel combination is administered with sunitinib (SU11248). In a further aspect, the CP-675,206-carboplatin-paclitaxel combination is administered with PF03512676 (CpG-7909).

  In another embodiment of the invention, the therapy is docetaxel (TAXOTERE) as second-line therapy for NSCLC in patients with locally advanced stage IIIb or metastatic stage IV after previously failing platinum-based chemotherapy And administration of CP-675,206. In one aspect, CP-675,206 is administered concurrently with docetaxel therapy. In other embodiments, CP-675,206 is administered after docetaxel therapy. In yet another aspect, the NSCLC comprises locally advanced stage IIIb or metastatic stage IV non-small cell lung cancer after previously failing platinum-based chemotherapy.

  In yet other embodiments, the invention includes treatment of NSCLC, the therapy comprising administration of CP-675,206 and erlotinib (TARCEVA) as second line therapy. In one aspect, CP-675,206 is administered concurrently with erlotinib. In other embodiments, CP-675,206 is administered after erlotinib therapy.

  In a further embodiment, the invention includes a second line therapy for NSCLC comprising administration of CP-675,206 and pemetrexed (ALIMTA). In one aspect, CP-675,206 is administered concurrently with pemetrexed. In other embodiments, CP-675,206 is administered after pemetrexed therapy. In yet another aspect, NSCLC is locally advanced stage IIIb. In yet another aspect, the NSCLC is metastatic stage IV non-small cell lung cancer after previously failing platinum-based chemotherapy.

  In other embodiments, the invention includes treatment of locally advanced stage IIIb or metastatic stage IV NSCLC after previously failing platinum-based chemotherapy and epidermal growth factor receptor-based therapy. In one aspect, CP-675,206 is administered as a single agent. In other embodiments, CP-675,206 is administered in combination with a therapeutic agent.

3. Colorectal cancer (CRC)
In one embodiment, the invention includes a method of treating colon and / or rectal cancer. In one embodiment, the method comprises administering a combination comprising CP-675,206 and fluorouracil (5FU) as first line therapy for CRC patients intolerant to oxaliplatin (ELOXATIN) or irinotecan (CAMPTO). . In other embodiments, the treatment comprises administering a combination of CP-675,206 and capecitabine (XELODA) as a first line therapy for patients intolerant to oxaliplatin or irinotecan.

  In other embodiments, the therapy comprises first line treatment of patients with metastatic cancer of the colon or rectum, including administration of CP-675,206 and FOLFOX (fluorouracil, leucovorin and oxaliplatin). In one aspect, CP-675,206 is administered concurrently with FOLFOX therapy. In other embodiments, CP-675,206 is administered after FOLFOX therapy.

  In other embodiments, the treatment includes adjuvant therapy for patients with stage III colon cancer undergoing complete resection of the primary tumor. In a further aspect, the therapy comprises administration of CP-675,206 and FOLFOX (fluorouracil, leucovorin and oxaliplatin). In one aspect, CP-675,206 is administered concurrently with FOLFOX therapy. In other embodiments, CP-675,206 is administered after FOLFOX therapy.

  In other embodiments, the therapy comprises first line treatment of patients with metastatic CRC, including administration of CP-675,206 and FOLFIRI (fluorouracil, leucovorin and irinotecan). In one aspect, CP-675,206 is administered contemporaneously with FOLFIRI therapy. In other embodiments, CP-675,206 is administered after FOLFIRI therapy.

  In other embodiments of the invention, the therapy comprises treatment of CRC, including administration of CP-675,206 and cetuximab (ERBITUX, ImClone). In one aspect, CP-675,206 is administered concurrently with cetuximab. In other embodiments, CP-675,206 is administered after cetuximab.

  In other embodiments, the invention encompasses a method of treating CRC, the method comprising administering CP-675,206 and a combination of fluorouracil and capecitabine as adjuvant therapy. Co-administration of a chemotherapeutic agent capable of mediating increased release of tumor antigens and CP-675,206 can mediate an increased immune response against the tumor, thereby providing a therapeutic benefit to patients suffering from it Is brought about.

4). Leukemia In one embodiment, the present invention includes a method of treating chronic myeloid leukemia (CML). In one aspect, the method comprises administering a combination of CP-675,206 and imatinib mesylate (GLEEVEC, Novartis) as first line therapy for CML.

  In other embodiments, the invention includes a method of treating chronic lymphocytic leukemia (CLL). In one aspect, the treatment comprises administration of CP-675,206 and imatinib mesylate as first line therapy.

5). Pancreatic cancer In one embodiment, the invention includes a method of treating pancreatic cancer, the method comprising administering a combination of CP-675,206 and gemcitabine (GEMZAR). In one aspect, the therapy is first line treatment of patients with locally advanced (unresectable stage II or III) adenocarcinoma of the pancreas. In other embodiments, the cancer is pancreatic metastatic (stage IV) adenocarcinoma. In yet another aspect, gemcitabine is administered concurrently with CP-675,206. In a further aspect, CP-675,206 is administered after administration of gemcitabine.

In one embodiment of the invention, CP-675,206 is administered after at least one course of treatment with gemcitabine. In one aspect, gemcitabine is administered intravenously at a dose of about 1000 mg / m ² once a week for up to 7 weeks or until it is necessary to reduce or refrain from administration due to toxicity. There is a one week rest period after the dosing phase during which no gemcitabine is administered. Subsequent gemcitabine dosing cycles consisted of i. v. Infusion followed by a one week rest period. In a further aspect, CP-675,206 is administered after the entire course of gemcitabine treatment (ie, 7 weeks of administration and 1 week of rest). In other embodiments, CP-675,206 is administered every 3 weeks thereafter. In yet another aspect, the combination of gemcitabine (eg, 3 weeks of administration followed by 1 week of rest) and CP-675,206 (eg, every 3 weeks) continues until the disease worsens or intolerant toxicity occurs. .

6). Breast cancer In one embodiment, the invention includes a method of treating locally advanced or triple receptor negative breast cancer. In one aspect, the method is first line therapy. In other aspects, the therapy comprises administering CP-675,206 and a taxane (eg, docetaxel and paclitaxel). In one aspect, CP-675,206 and taxane are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of the taxane.

  In other embodiments, the therapy includes adjuvant treatment of breast cancer, including administration of CP-675,206 and cyclophosphamide, doxorubicin and taxane. In one aspect, the therapy includes adjuvant therapy.

  In other embodiments, the therapy is CP-675,206, and tamoxifen (NOVALDEX), anastrazole (ARIMIDEX), letrozole (FEMARA), exemestane (AROMASIN) or fulvestrant (FASLODEX), or a combination thereof. Including administration. In one aspect, the therapy is adjuvant therapy for metastatic breast cancer.

  In another embodiment of the invention, breast cancer therapy comprises the administration of CP-675,206 and trastuzumab (HERCEPTIN). In one aspect, the antibodies are administered simultaneously. In other embodiments, CP-675,206 is administered after trastuzumab is administered. In a further aspect, the CP-675,206-trastuzumab combination therapy comprises adjuvant therapy and first line therapy for metastatic breast cancer.

  In still other embodiments, the therapy comprises administering CP-675,206 and bevacizumab. In one aspect, CP-675,206 and bevacizumab are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of bevacizumab.

  In one embodiment of the invention, the therapy for treating breast cancer comprises administering CP-675,206 and cetuximab. In one aspect, CP-675,206 and cetuximab are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of cetuximab.

  In other embodiments of the invention, the therapy for treating breast cancer comprises administering CP-675,206 and axitinib. In one aspect, CP-675,206 and axitinib are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of axitinib.

7). Ovarian Cancer In one embodiment, the invention includes a method of treating ovarian cancer. In one embodiment, the therapy comprises administration of CP-675,206 and carboplatin and paclitaxel. In one aspect, CP-675,206 is administered concurrently with carboplatin and paclitaxel. In other embodiments, CP-675,206 is administered after administration of carboplatin and paclitaxel. In yet another aspect, the treatment is a first line treatment for advanced cancer of the ovary.

  In other embodiments of the invention, the therapy comprises second-line therapy for patients who have worsened after paclitaxel-based therapy (eg, suggested by tumor assessment, doubling of CA-125, CT scan, etc.). Including. In one aspect, the therapy comprises administration of CP-675,206 as a single agent. In other embodiments, the therapy is altretamine, anastrozole, bevacizumab, carboplatin, cisplatin, cyclophosphamide, liposomal doxorubicin, docetaxel, gemcitabine, ifosfamide, irinotecan, letrozole, melphalan, oral etoposide, oxaliplatin, tamoxifen, Administration of CP-675,206 in combination with an agent selected from the group consisting of topotecan, and vinorelbine, and any combination thereof.

8). Gastric cancer In one embodiment of the invention, the cancer comprises gastric cancer and the therapy comprises administering CP-675,206 and irinotecan. In one aspect, CP-675,206 and irinotecan are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of irinotecan.

  In other embodiments, the treatment comprises administration of CP-675,206, fluorouracil and leucovorin. In one aspect, CP-675,206, fluorouracil and leucovorin are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of fluorouracil and leucovorin.

9. Liver cancer In one embodiment of the invention, the cancer comprises liver cancer and the therapy comprises administering CP-675,206 and doxorubicin, ifosfamide and vincristine. In one aspect, CP-675,206 and doxorubicin, ifosfamide and vincristine are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of doxorubicin, ifosfamide and vincristine.

  In other embodiments, the cancer is liver cancer and the therapy comprises administering CP-675,206, doxorubicin, and vincristine. In one aspect, CP-675,206, doxorubicin, and vincristine are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of doxorubicin and vincristine.

10. Metastatic lesions In one embodiment of the invention, CP-675,206 is administered to treat metastases, which metastases are to the brain and / or bone. In one aspect, CP-675,206 is used to treat brain and bone metastases regardless of the location of the primary tumor where the cancer has metastasized.

  In one aspect, a combination of anti-CTLA4 antibodies and removal by surgical excision and / or radiation therapy, preferably further combined with CP-675,206, is used to treat brain metastases. That is, if there are multiple metastases and / or lesions greater than about 3 cm in diameter, whole brain radiation can be administered followed by administration of anti-CTLA4 antibody. In a further aspect, the antibody is administered prior to irradiation. In a further aspect, 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, more preferably at least about 15 mg / kg. In other embodiments, the antibody is administered every 3 weeks, more preferably every 4 weeks, and even more preferably every 3 months.

  In one embodiment, if there are less than about 5 lesions in the brain and all lesions are less than about 3 cm in maximum diameter, stereotactic radiosurgery (SRS) is performed followed by administration of anti-CTLA4 antibody. In one aspect, the antibody is administered prior to SRS. In other embodiments, the antibody is administered before and after SRS.

  In other embodiments, surgery, whole brain radiation and SRS can be combined in any order to treat brain metastases, which is further combined with antibody therapy. In one aspect, antibody therapy is performed after irradiation / surgery / SRS. Alternatively, antibody therapy can be performed prior to irradiation / surgery / SRS and before or after such therapy.

  This will be appreciated by those skilled in the art because brain metastases are common in melanoma. SRS can provide local control of brain metastases, but poor management of systemic disease causes most patients to die from systemic metastases and / or re-seeding of the CNS. Thus, in one embodiment, the present invention provides a combination therapy that manages local brain metastasis, prevents CNS reseeding, and controls systemic disease, thereby requiring a patient Provides therapeutic benefits.

11. Bladder Cancer In one embodiment, CP-675,206 is administered in combination with BCG to treat bladder cancer. In one aspect, CP-675,206 and BCG are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of BCG.

  In other embodiments, the treatment of bladder cancer comprises administering CP-675,206 and gemcitabine and cisplatin. In one aspect, CP-675,206, gemcitabine and cisplatin are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of gemcitabine and cisplatin.

12 Melanoma The present invention encompasses a combination of CP-675,206 and interferon alpha to treat melanoma. In one aspect, CP-675,206 and interferon alpha are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of interferon alpha. In a further aspect, interferon alpha is administered as a high dose.

13. Multiple myeloma In one embodiment of the present invention, treatment of multiple myeloma comprises administration of CP-675,206 and bortezomib. In one aspect, CP-675,206 and bortezomib are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of bortezomib.

  In other embodiments, the therapy comprises administration of CP-675,206 and dexamethasone and thalidomide. In one aspect, CP-675,206, dexamethasone and thalidomide are administered simultaneously. In other embodiments, CP-675,206 is administered after administration of dexamethasone and thalidomide.

  In alternative embodiments of the invention discussed above, anti-CTLA4 antibodies other than CP-675,206 can be used in the methods of the invention. US patent application 09 / 472,087, now published as US Pat. No. 6,682,736; International application PCT / US99 / 30895 (published as WO 00/37504 on June 29, 2000); 10 / 612,497 (published on Nov. 18, 2004 as U.S. Patent Application Publication No. 2004/0228858); U.S. Patent Application No. 10 / 776,649 (U.S. Publication No. 2004/0228861, 2004) Published on Nov. 18); international application PCT / US00 / 23356 (published on Mar. 1, 2001 as WO 01/14424) (eg also known as MDX-010 in Medarex, Princeton, NJ, herein Antibody 10D1) called ipilimumab; International application P T / US99 / 28739 (published on June 8, 2000 as WO 00/32231); U.S. Pat. Nos. 5,811,097, 5,855,887, 6,051,227 and 6,207. Linsley et al., US Pat. No. 5,844,095; International Application PCT / US92 / 05202 (published on Jan. 7, 1993 as WO 93/00431); US Patent Application 10 / 153,382 ( Published on May 8, 2003 as U.S. Patent Application Publication No. 2003/0086930; U.S. Patent Application No. 10 / 673,738 (published on Feb. 24, 2005 as U.S. Patent Application Publication No. 2005/0042223) U.S. Patent Application No. 11 / 085,368 (US Patent Application Publication No. 2005/0226875 Published on May 13); US Patent Application No. 60 / 624,856 (filed November 4, 2004); US Patent Application No. 60 / 664,364 (filed March 23, 2005); US Patent Application No. 60 / 664,653 (filed on Mar. 23, 2005); U.S. Patent Application No. 60 / 697,082 (filed on Jul. 7, 2005); U.S. Patent Application No. 60 / 711,707 (August 2005) Alternative antibodies are described herein, including those described in the application on Jan. 26. More preferably, the antibodies are described in US Pat. No. 6,682,736 and WO01 / 14424. More preferably, the antibody is 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. Antibodies having heavy and light chain amino acid sequences of an antibody selected from the group consisting of.

B. Those skilled in the art, having the disclosure provided herein, for the immunopotentiating effects of CTLA4 blockade, can be used by the present invention to treat a variety of diseases, disorders or conditions associated with pathogens. It will be appreciated that an immune response against a pathogen provides therapeutic benefit, including administration of an anti-CTLA4 antibody in combination with This includes, but is not limited to, bacterial, viral, fungal, parasitic, and other pathogenic diseases. The treatment of infectious diseases, including blockade with anti-CTLA4 antibodies, is discussed, for example, in WO 03/086459, published Oct. 23, 2003.

  Similar to the use of CTLA4 blockade in combination to treat the tumors discussed above, blocking with anti-CTLA4 antibodies is used in combination with vaccines and other therapeutic agents, including standard therapies, A disease, disorder or condition involving a pathogen, or a toxin derived therefrom, can be treated. That is, previous studies have shown that blockade with anti-CTLA4 antibodies may be useful in the treatment of infectious parasites (McCoy et al., J. Exp. Med. 186: 183-187 ( 1997); Murphy et al., J. Immunol. 161: 4153-4160 (1998)). Examples of pathogens where this therapeutic approach may be particularly useful include, but are not limited to, HIV, hepatitis (types A, B, and C), influenza, herpes, giardia, malaria, leishmania, yellow grape There are cocci, Pseudomonas aeruginosa, and Helicobacter pylori.

  Some examples of viruses that can be treated by the methods of the present invention include hepatitis (types A, B, or C), herpes viruses (eg, VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flavivirus, echovirus, Ebola virus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rota Virus, measles virus, rubella virus, parvovirus, vaccinia virus, pox virus, HTLV virus, dengue virus, papilloma virus, molluscum virus, poliovirus, rabies virus There are Ruth, JC virus and Arbovirus encephalitis virus.

  In one embodiment, bacterial infections treatable by the methods of the invention include Chlamydia, Rickettsia bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia , Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Helicobacter, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria (eg Borrelia burgdorferi).

  In other embodiments, fungal infections treatable according to the methods of the present invention include, but are not limited to, Candida (Albicans, Crusei, Glabrata, Tropicalis, etc.), Cryptococcus neoformans, Aspergius (Fumigatus, Niger, etc.), There are the genus Kempi (Kemobi, Yumike Kabi, Kumonosukabi), Sporotrix Schenky, Blast Mrs. Dermatidis, Paracoccidioides braziliansis, Coccidioides imimitis and Histoplasma capsularsum.

  In still other embodiments, parasitic infections treatable by the methods of the present invention include, among others, Shigella amoeba, colonic barantidium, negrelia forelli, Acanthamoeba species, rumble flagellates, Cryptosporidium species, Pneumocystis carinii There are protozoan malaria parasites, Babesia microchis, trypanosoma brucei, cruise trypanosomes, donovan leishmania, toxoplasma parasites and brazilian helminths.

1. HIV / AIDS
Studies have suggested that CTLA4 blockade may be useful in the treatment of viral diseases, and more specifically, studies in rhesus monkeys have demonstrated anti-CTLA4 in combination with antiretroviral therapy ("ART") (ie , Ipilimumab) has been shown to be associated with an increased antiviral response. See Hryniewitz et al., Blood 108: 3834-3842 (2006). More specifically, CTLA4 blockade not only reduced viral load and increased virus-specific effector T cells, but also immunosuppression in SIV _mac251 infected macaques that also received ART (didanocin, stavudine and tenofovir [PMPA]). The levels of sex molecules (eg, transforming growth factor β [TGF-β] and indoleamine 2,3-dioxygenase [IDO]) were also reduced. These data suggest that anti-CTLA4 antibodies in combination with antiviral therapy can provide a therapeutic benefit in the treatment of HIV infection in humans.

  In one embodiment of the invention, the anti-CTLA4 antibody, specifically CP-675,206, and pharmaceutically acceptable salts, solvates and derivatives thereof are administered alone or as part of a combination therapy. Can do. Accordingly, within the scope of the invention are embodiments that include, in addition to a compound of the invention, co-administration of one or more additional therapeutic agents and compositions containing the same.

  Such multi-drug therapy, often referred to as combination therapy, can be used to treat human immunodeficiency virus HIV and related pathogenic retrovirus infections in patients in need of treatment or at risk of becoming such patients and Can be used in the treatment and prevention of proliferation. The ability of such retroviral pathogens to evolve into a strain that is resistant to any monotherapy within a relatively short period of time is well known in the literature. The recommended treatment for HIV is a combination drug treatment called highly active antiretroviral therapy (“HAART”). In HAART, three or more HIV drugs are used in combination. Thus, in the therapeutic methods and pharmaceutical compositions of the present invention, the compounds of the present invention can be used in the form of monotherapy, but one or more additional therapeutics such as those described in more detail herein. The methods and compositions described above can also be used in the form of combination therapy in which an anti-CTLA4 antibody is co-administered in combination with an agent.

  Therapeutic agents that can be used in combination with anti-CTLA4 antibodies include, but are not limited to, those useful as HIV protease inhibitors (PI), non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside / nucleotide reversals. Inhibitors of transcriptase inhibitors (NRTI), CCR5 antagonists, agents that inhibit the interaction of gp120 and CD4, other agents that inhibit entry of HIV into target cells (such as fusion inhibitors), inhibition of HIV integrase There are agents, RNase H inhibitors, prenylation inhibitors, maturation inhibitors that act by interfering with the production of HIV capsid proteins, compounds useful as antiinfectives, and others described below.

  It will be appreciated by those skilled in the art that the combination drug treatment described herein above may include two or more compounds having the same or different mechanisms of action. Thus, by way of example only, a combination comprises a compound of the invention and one or more NRTIs; one or more NRTIs and PIs; one or more NRTIs and other CCR5 antagonists; PI; PIs and NNRTIs; Etc. may be included.

  Examples of PI include, but are not limited to, amprenavir (141W94), CGP-73547, CGP-61755, DMP-450 (mozenavir), nelfinavir, ritonavir, saquinavir (invilase), lopinavir, TMC-126 , Atanazavir, Parinavir, GS-3333, KN I-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-14690, ABT-378, DMP-450, AG-1776, MK-944, becanavir (formerly known as VX-478, GW640385), indinavir, tipranavir, TMC-114, DPC-681, DP C-684, phosamprenavir calcium (Lexiva), benzenesulfonamide derivatives disclosed in WO03 / 053435, R-944, Ro-03-34649, VX-385, GS-224338, OPT-TL3, PL- 100, PPL-100, SM-309515, AG-148, DG-35-VIII, DMP-850, GW-5950X, KNI-1039, L-756423, LB-71262, LP-130, RS-344, SE- 063, UIC-94-003, Vb-19038, A-77003, BMS-182193, BMS-186318, SM-309515, JE-2147, and GS-9005.

  Examples of NRTI include, but are not limited to, abacavir, GS-840, lamivudine, adefovir dipivoxil, β-fluoro-ddA, zalcitabine, didanosine, stavudine, zidobosine, tenofovir (9- [9 (R) -2- ( Phosphonomethoxy) propyl] adenine; PMPA), tenofovir disoproxil fumarate (Viread; Gliad Sciences), amdoxovir (DAPD), SPD-754, SPD-756, racivir, river set (DPC-D) 817), MIV-210 (FLG), β-L-Fd4C (ACH-126443), MIV-310 (alovudine, FLT), dOTC, DAPD, entecavir, GS-7340, emtricitabine (FTC). .

  Examples of NNRTI include, but are not limited to, efavirenz, HBY-097, nevirapine, TMC-120 (dapivirine), TMC-125, etalavirin, delavirdine, DPC-083, DPC-961, coupler bilin, Rilpivirine, 5-{[3,5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl] oxy} isophthalonitrile, or a pharmaceutically acceptable salt, solvate thereof, or Derivatives: GW-678248, GW-695634, MIV-150, calanolide, and tricyclic pyrimidinone derivatives disclosed in WO 03/062238.

  Examples of 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-endo- {8- [ (3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7 -Tetrahydro-1H-imidazo [4,5-c] pyridine-5-ca Boxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, methyl 3-endo- {8-[(3S) -3- (acetamido) -3- (3-fluorophenyl) propyl] -8-azabicyclo [ 3.2.1] Oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-3H-imidazo [4,5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt thereof Salt, solvate or derivative, ethyl 1-endo- {8-[(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct -3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt or solvate thereof Or N-{(1S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine- 1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide) or a pharmaceutically acceptable salt, solvate or derivative thereof. .

  In one embodiment, an anti-CTLA4 antibody, preferably CP-675,206, is administered in combination with maraviroc. In other embodiments, the anti-CTLA4 antibody / maraviroc combination therapy comprises evaluating whether it is expressed on the cell surface of the patient. In yet other embodiments, the therapy assesses the tropism of HIV co-receptors (ie, CXCR4 or CCR5), and the patient has a CCR5 co-receptor, CXCR4 co-receptor, or both (dual Determining whether the patient is infected with HIV using (/ mixed tropism) and determining whether the patient is a candidate for maraviroc therapy. In other embodiments, the co-receptor tropism assay is TROFILE (Monogram Biosciences, Inc., San Francisco, Calif.). This is because treatment with maraviroc inhibits cell entry mediated by CCR5. Thus, by evaluating CCR5 expression by the patient's cells and / or assessing the co-receptor tropism of the virus, the treatment choice for the patient is optimized.

  Examples of entry and fusion inhibitors include, but are not limited to, BMS-806, BMS-488043, 5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl ] -1-Methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid methylamide and 4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazine-1 -Yl] -1-methyl-2-oxo-ethoxy} -3-methoxy-N-methyl-benzamide, enfuvirtide (T-20), shifuvirtide SP-01A, T1249, PRO 542 , AMD-3100, soluble CD4, compounds disclosed in JP2003171381, and JP200319137 That there is a compound.

  Examples of inhibitors of HIV integrase include, but are not limited to, 1,5-naphthyridine-3-carboxamide derivatives disclosed in L-000870810, GW-810781, WO03 / 062204, WO03 / 047564 Compounds disclosed in WO 03/049690, 5-hydroxypyrimidine-4-carboxamide derivatives disclosed in WO 03/035076, MK-0518 (5- (1,1-dioxo-disclosed in WO 0316315) 1,2-thiazinan-2-yl) -N- (4-fluorobenzyl) -8-hydroxy-1,6-naphthyridine-7-carboxamide), GS-9137 (JTK-303).

  Examples of prenylation inhibitors include, but are not limited to, HMG CoA reductase inhibitors such as statins (eg, atorvastatin).

  Examples of maturation inhibitors include 3-O- (3'3'-dimethylsuccinyl) betulinic acid (otherwise known as PA-457) and αHGA.

II. Dosage regimes The dosage regimens may be adjusted to provide the optimum desired response. For example, as indicated by the urgency of the treatment situation, a single bolus can be given, several divided doses can be given over time, or the dose can be increased or decreased proportionally You can also. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dosage for a mammalian subject to be treated, each unit with the required pharmaceutical carrier so as to provide the desired therapeutic effect. Containing a predetermined amount of active compound calculated in The designation of a unit dosage form of the present invention combines (a) the unique characteristics of the antibody and the specific therapeutic or prophylactic effect to be realized, and (b) such active compounds for the treatment of susceptibility in an individual. Determined by technology-specific limitations and depend directly on them.

  An exemplary, non-limiting range for a therapeutically effective amount of ticilimumab administered according to the present invention is at least about 1 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, greater than about 10 mg / kg, Or at least about 15 mg / kg, such as about 1-30 mg / kg, or such as about 1-25 mg / kg, or such as about 1-20 mg / kg, or such as about 5-20 mg / kg. Yes, or for example about 10-20 mg / kg, or for example about 15-20 mg / kg, or for example about 15 mg / kg. Note that dosage values may vary depending on the type and severity of the alleviating condition and may include single or multiple doses. For any particular subject, the specific dosage regimen should be adjusted in the course of the individual needs and the professional judgment of the person performing or directing the administration of the composition, and the administration indicated herein It is further understood that the range of amounts is exemplary only and does not limit the scope or practice of the claimed composition. It should be understood that determination of suitable administration methods for antibody administration is well known in the relevant art and is encompassed by those of ordinary skill in the art after obtaining the teachings disclosed herein.

  In one embodiment, CP-675,206 is administered as an intravenous formulation that is a sterile aqueous solution comprising about 5-20 mg / ml antibody in a suitable buffer system.

  In one embodiment, for low dose administration, part of the administration is by intravenous bolus administration of the antibody formulation and the rest by infusion. For example, an intravenous injection of 0.01 mg / kg of antibody can be performed as a bolus, and the remainder of a predetermined antibody dose can be administered by intravenous injection. In other embodiments, the entire low dose is administered as a single bolus injection. At high doses, eg 3 mg / kg, no antibody is administered as a bolus dose, but the entire dose is administered by infusion. For example, a predetermined dose of antibody can be administered over a period of about 1.5 hours to about 5 hours.

  The present invention relates to the administration of a combination of an anti-CTLA4 antibody and at least one therapeutic agent. In one embodiment, the antibody is CP-675,206. In alternative embodiments of the invention, the antibody is selected from a variety of anti-CTLA4 antibodies, including but not limited to ipilimumab. In one aspect, the antibody is ipilimumab and the dosage is about 3 mg / kg. In other embodiments, the dose of ipilimumab is at least about 10 mg / kg.

  In one embodiment of the invention, the antibody (eg, CP-675,206, ipilimumab, etc.) is administered about every 3 weeks, more preferably about 4 cycles, and then every 3 months thereafter. In one aspect of this embodiment, the antibody is administered at about 10 mg / kg.

  One skilled in the art will appreciate that the combination of CP-675,206 and the therapeutic agent can be administered simultaneously, or that the antibody and therapeutic agent can be administered at different times. For example, in one embodiment, the antibody is administered as a single injection and / or infusion, and the therapeutic agent (eg, gemcitabine) is administered once a day before, during, or after the start of antibody administration. However, the present invention is not limited to any particular dose or method of administration of a therapeutic agent. Rather, the optimal dose, route or mode of administration for administration of the antibody and therapeutic agent can be readily determined by those skilled in the relevant art using well-known methods.

  For example, single or multiple administrations of the antibody can be performed. Alternatively, administration can be performed at least once, or at least 3, 6 or 12 times. Administration is, for example, every 2 weeks, every 3 weeks, every month, every 20 days, every 25 days, every 28 days, every 30 days, every 40 days, every 6 weeks, every 50 days, every 2 months , Every 70 days, every 80 days, every 3 months, every 6 months, or every year. In one aspect, the antibody is administered once every 3 weeks, preferably 4 cycles, and then every 3 months thereafter. In addition, the second therapeutic agent can be administered daily, several times or once a day, weekly, biweekly, every 3 weeks, every 4 weeks, every month, every 3 months, every 6 months, It can be administered once a year or at any other time period that will provide a therapeutic benefit to the patient as determined by a skilled physician.

  In one aspect, CP-675,206 is administered once a month. In other embodiments, CP-675,206 is administered every 3 months. In yet another aspect, ipilimumab is administered once a month.

  Antibodies can be administered until the disease worsens or intolerant toxicity occurs, or up to 12 consecutive cycles, whichever is shorter. The antibody can also be administered using a dosing regimen that includes a loading dose followed by a lower dose. The administration of at least one repeated course, more preferably several cycles of antibody and therapeutic agent, would benefit from the recurrence of the tumor and the previous administration of a combination of anti-CTLA4 antibody and other therapeutic agent. Or to patients who have not previously been administered an antibody or therapeutic agent in combination.

  In one embodiment, a single intravenous injection comprising CP-675,206 is performed every 28 days at a dose of about 3 mg / kg. In other embodiments, the anti-CTLA4 antibody is intravenously administered to the patient every 3 weeks at a dose of about 3 mg / kg, preferably about 6 mg / kg, more preferably about 10 mg / kg, preferably about 15 mg / kg. It is administered internally. After 4 doses, the antibody is then administered every 3 months.

  The invention encompasses administration of an anti-CTLA4 antibody, preferably CP-675,206, in combination with a wide range of agents. One of ordinary skill in the art will understand that after having learned the teachings provided herein, any method of administration recognized in the art for an agent can be used. Methods for administering chemotherapeutic agents and other agents described herein include, but are not limited to, “Cancer: Principles and Practice of Oncology”, 7th edition, edited by DeVita, Hellman, and Rosenberg, Lippincott, Williams & Wilkins, 2004, as well as “Cancer Chemotherapy and Biotherapy Principles and Practice”, 4th edition, edited by Chabner, Longo, Lippincott, Williams & Wilkins, 2005. it can. In addition, many of the agents disclosed herein can be administered based on FDA approved drug labeling instructions. Such labeling instructions are readily and publicly available from the websites of the Department of Health and Sciences, the US Food and Drug Administration, and the Center for Drug Evaluation and Research, and are searched according to drug name or active ingredient. can do. Accordingly, those of skill in the art will understand the methods of administration used in combination therapy for various diseases, including administration of anti-CTLA4 antibodies and therapeutic agents. As is known in the art, dosages can be adjusted based on, among other factors, toxicity, and if any, therapeutic efficacy. Accordingly, methods for administering a number of chemotherapeutic agents and other agents associated with cancer treatment are well known in the art and are described in numerous publications, including those described herein. Yes. For an exemplary dosing table for various chemotherapeutic agents, see International Application PCT / US03 / 12802 (WO 03/090686, Nov. 6, 2003, which is incorporated herein by reference for all purposes). (Published in US Pat. No. 5,849, pp. 72-74).

  In some embodiments, the antibody-therapeutic agent combination can also be administered as an adjuvant therapy to increase tumor cell sensitivity or otherwise confer therapeutic benefit to the patient, or It can also be administered to the patient as neoadjuvant therapy prior to surgery, radiation therapy, or any other treatment.

  Further, in some embodiments, the combination may be administered as a first line therapy, or as a second or third line therapy, such as, but not limited to, after the previous (s) therapy has failed. it can. Alternatively, the combination can be administered after the initial treatment, simultaneously with the first line therapy and / or at any time during the therapy. Thus, the combination of anti-CTLA4 antibody and therapeutic agent is a systemic adjuvant therapy using other therapeutic agents (eg, temozolomide, leuprolide, paclitaxel, imatinib mesylate, gefitinib, etc.) after previous therapy has failed Can have a therapeutic effect after failing. Accordingly, as will be appreciated by one of ordinary skill in the art based on the disclosure provided herein, the present invention is not limited thereto, but includes different therapeutic agents (eg, chemotherapeutic agents, antibodies, immunomodulators). Including administration of anti-CTLA4 antibodies and therapeutic agents in combination with or subsequent to further therapy including substances, cytokines, etc.).

III. Anti-CTLA4 Antibodies The present invention encompasses alternative embodiments that use CTLA4 antibodies in addition to CP-675,206. In one embodiment, the CTLA4 antibody comprises a heavy chain and the amino acid sequence of _VH comprises the amino acid sequence set forth in SEQ ID NOs: 3, 15, and 27. In still other embodiments, the V _L of the CTLA4 antibody comprises the amino acid sequence set forth in SEQ ID NOs: 9, 21, and 33. More preferably, the V _H and V _L regions of the antibody have the amino acid sequences shown in SEQ ID NO: 3 (V _H 4.1.1) and SEQ ID NO: 9 (V _L 4.1.1), respectively; SEQ ID NO: 15 ( V _H 4.13.1) and the amino acid sequence shown in SEQ ID NO: 21 (V _L 4.13.1); SEQ ID NO: 27 (V _H 11.2.1) and SEQ ID NO: 33 (V _L 11.2. The amino acid sequence shown in 1) is included. Most preferably, the antibody is CP-675,206 comprising the heavy and light chain amino acid sequences of antibody 11.2.1 (ticilimumab).

  In still other embodiments, the heavy chain amino acid sequence comprises an amino acid sequence encoded by a nucleic acid comprising the nucleic acid sequences set forth in SEQ ID NOs: 1, 13, and 25. In yet other embodiments, the light chain comprises an amino acid sequence encoded by a nucleic acid comprising the nucleic acid sequences shown in SEQ ID NOs: 7, 19, and 31. More preferably, the heavy and light chains are nucleic acid sequences shown in SEQ ID NO: 1 (heavy chain 4.1.1) and SEQ ID NO: 7 (light chain 4.1.1), respectively; SEQ ID NO: 13 (heavy chain 4 .13.1) and the nucleic acid sequence shown in SEQ ID NO: 19 (light chain 4.13.1); SEQ ID NO: 25 (heavy chain 11.2.1) and SEQ ID NO: 31 (light chain 11.2.1) respectively. Comprising the amino acid sequence encoded by the nucleic acid comprising the nucleic acid sequence shown.

In addition, the antibody may comprise a human CDR amino acid sequence derived from the V _H 3-30 or 3-33 gene, or a heavy chain amino acid sequence comprising conservative substitutions or somatic mutations therein. It is understood that the V _H 3-33 gene encodes FR1 to FR3 of the heavy chain variable region of the antibody molecule. Therefore, the present invention provides 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 At least 85%, more preferably at least 90%, more preferably at least 91%, much more preferably at least 94%, even more preferably at least 95%, more preferably at least 97% with the FR1 to FR3 sequence of the antibody to be Much more preferably, it includes antibodies having at least 98%, more preferably at least 99%, most preferably 100% identity.

  The antibody may further comprise a CDR region in its light chain derived from the A27 or O12 gene or alternatively 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, may comprise a CDR region of an antibody selected from the group consisting of ipilimumab.

In other embodiments of the invention, the antibody inhibits binding of CTLA4 to B7-1, B7-2, or both. Preferably, the antibody has an IC _{50 of} about 100 nM or less, more preferably about 10 nM or less, such as about 5 nM or less, more preferably about 2 nM or less, or even more preferably, for example, 1 nM or less with B7-1. Binding can be inhibited. Similarly, an antibody has an IC _{50 of} about 100 nM or less, more preferably about 10 nM or less, such as much more preferably about 5 nM or less, even more preferably about 2 nM or less, or even more preferably 1 nM or less. 2 can be inhibited.

Furthermore, in other embodiments, the anti-CTLA4 antibody is about 10 ⁻⁸ or more, more preferably about 10 ⁻⁹ or more, more preferably about 10 ⁻¹⁰ or more, and much more preferably about 10 ⁻¹¹ or more. Has binding affinity for CTLA4.

  The anti-CTLA4 antibody is 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. Antibodies that compete for binding with antibodies having heavy and light chain amino acid sequences are included. Furthermore, anti-CTLA4 antibodies can compete for binding with the antibody ipilimumab.

  In other embodiments, the antibody is preferably antibody 4.1.1, 4.13.1, 4.14.3, 6.1.1, or 11.2.1 (CP-675,206). Cross-compete with antibodies having heavy and light chain sequences, variable heavy and variable light chain sequences, and / or heavy and light chain CDR sequences. For example, the antibody is 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) Can bind to epitopes to which antibodies having heavy and light chain amino acid sequences, variable sequences and / or CDR sequences bind. In other embodiments, the antibodies cross-compete with antibodies having MDX-D010 heavy and light chain sequences or antigen binding sequences.

  In other embodiments, 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), CDR- of an antibody selected from the group consisting of 11.6.1, 11.7.1, 12.3.1.1, and 12.9.1.1 1, a heavy chain comprising the CDR-2 and CDR-3 amino acid sequences, and a light chain comprising the CDR-1, CDR-2 and CDR-3 amino acid sequences, or other nonpolar residues due to other nonpolar residues Selected from the group consisting of substitution of groups, substitution of polar charged residues by other polar uncharged residues, substitution of polar charged residues by other polar charged residues, and substitution of structurally similar residues Conservative change; selected from the group consisting of substitution of polar uncharged residues with polar charged residues and substitution of polar residues with nonpolar residues To implement the invention using an anti-CTLA4 antibody comprising an array having a change from the additional and CDR sequences selected from the group consisting of deletion; nonconservative substitutions.

  In a further embodiment of the invention, the antibody comprises fewer than 10, 7, 5, or 3 amino acid changes from the germline sequence in the framework or CDR regions. In other embodiments, the antibody comprises less than 5 amino acid changes in the framework regions and less than 10 changes in the CDR regions. In one preferred embodiment, the antibody comprises less than 3 amino acid changes in the framework regions and less than 7 changes in the CDR regions. In a preferred embodiment, the change in the framework region is conservative and the change in the CDR region is a somatic mutation.

  In other embodiments, the antibody is directed to antibody 3.1.1, 4.1.1, 4.8.1, 4.10 over the full-length sequence of heavy and light chains, or over separate heavy or light chains. 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 sequence and at least 80%, more preferably at least 85%, much more preferably at least 90%, even more preferably at least 94%, preferably at least 95%, more preferably Have at least 99% sequence (eg, amino acids, nucleic acids, or both) identity or sequence similarity. Even more preferably, the antibody is 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, the weight of the antibody selected from ipilimumab Has 100% sequence identity or sequence similarity with the heavy or light chain over the chain and light chain or separately.

  In yet other embodiments, the antibody has heavy and light chain regions having the amino acid sequence of ipilimumab (formerly known as MDX-010).

In other embodiments, the antibody spans the full length sequences of heavy and light chains, or across heavy or light chains separately, of germline V _κ A27, germline V _κ O12, and (V _H 3-33 loci). At least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 94%, more preferably at least 95%, and most preferably at least 99, with the sequence of the germline DP50 (which is an allele). % Sequence identity or sequence similarity. Even more preferably, the antibody has 100% sequence identity or sequence similarity across the heavy chain sequence of germline DP50 and / or with the light chain sequence of germline A27, or germline O12.

  In one embodiment, the antibody is directed to antibody 3.1.1, 4.1.1, 4.8.1 over the heavy and light chain variable region sequences or over the heavy or light chain variable region sequences separately. 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, sequence of ipilimumab and at least 80%, more preferably at least 85%, much more preferably at least 90%, even more preferably at least 94%, preferably at least 95 %, More preferably at least 99% sequence (eg, amino acid, nucleic acid or both) identity or sequence similarity. Much preferably, the antibody is 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, weight of antibody selected from ipilimumab Has 100% sequence identity or sequence similarity with the heavy or light chain sequences over the chain and light chain variable region sequences or separately.

In other embodiments, the antibody spans the heavy chain variable region sequence (which is an allele of the V _H 3-33 locus), the heavy chain variable sequence of heavy chain germline DP50, or the germline V _κ A27, or germline. a light chain variable sequence at least 80% sequence V _kappa O12, more preferably at least 85%, much more preferably at least 90%, more preferably at least 94%, more preferably at least 95%, much more preferably at least 99% Have sequence identity or sequence similarity. More preferably, the heavy chain variable sequence of the antibody has 100% sequence identity or sequence similarity with the germline DP50 sequence or with the germline A27 or germline O12 light chain sequence.

  In one embodiment of the invention, the antibody is 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, FR1 to FR4 of ipilimumab FR1 to FR4 heavy chain, light chain, or both sequences with region sequences and at least 80%, more preferably at least 85%, much more preferably at least 90%, even more preferably at least 95%, more preferably at least Has 99% sequence identity or sequence similarity. Even more preferably, the antibody spans the sequences of FR1 to FR4 heavy chain, light chain, or both, with 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, 12.9.1.1, CP-675, 206, and 100% sequence identity or sequence similarity with ipilimumab.

  In another embodiment of the invention, the antibody is at least 80%, more preferably at least 85%, and much more preferably at least 90% with the heavy chain sequence of FR1 to FR3 having the FR1 to FR3 region sequence of germline DP50. More preferably it has at least 95% sequence identity or sequence similarity, more preferably at least 99%, and most preferably about 100%.

In yet another embodiment of the present invention, the antibody germline V _kappa A27 or at least 80% with the light chain sequence of germline V _kappa FR1 from FR4 having FR1 from FR4 region sequences of O12,, more preferably at least 85 %, Much more preferably at least 90%, even more preferably at least 95%, more preferably at least 99%, most preferably about 100% of sequence identity or sequence similarity.

  In one embodiment of the invention, the antibody is 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, the heavy chain of ipilimumab, At least 80%, more preferably at least 85%, much more preferably at least 90%, even more preferably at least 95%, more preferably at least at least 80% of the light chain, or both CDR-1, CDR-2 and CDR-3 sequences Has 99% sequence identity or sequence similarity. Even more preferably, the antibody spans the CDR-1, CDR-2 and CDR-3 sequences of heavy chain, light chain, or both, 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 100% sequence identity or sequence similarity with ipilimumab.

  In other embodiments of the invention, the antibody is at least 80%, more preferably at least 85%, and much more heavy chain CDR-1 and CDR-2 sequences having the germline DP50 CDR-1 and CDR-2 sequences. Preferably it has at least 90%, more preferably at least 95%, more preferably at least 99%, most preferably about 100% sequence identity or sequence similarity.

In yet another embodiment of the present invention, the antibody germline V _kappa A27 or light chain having CDR-1, CDR-2 and CDR-3 sequences of germline _{V κ O12 CDR-1, CDR} -2 and, At least 80%, more preferably at least 85%, much more preferably at least 90%, even more preferably at least 95%, more preferably at least 99%, most preferably about 100% sequence identity or sequence with a CDR-3 sequence Similarity.

  Examples of antibodies that can be used in the present invention and methods for making them are published inter alia as US patent application Ser. No. 09 / 472,087, now US Pat. No. 6,682,736; International Application PCT / US00 / 23356. (Published on March 1, 2001 as WO 01/14424) (eg, antibody ipilimumab, also known as MDX-010 in Medarex, Princeton, NJ); International Application PCT / US99 / 28739 (June 2000 as WO 00/32231) Published on the 8th); U.S. Pat. Nos. 5,811,097, 5,855,887, 6,051,227 and 6,207,156, each of which is incorporated by reference Is incorporated herein. Information about the amino acid and nucleic acid sequences for these antibodies is provided herein, but additional information can be found in US Pat. No. 6,682,736, as well as in WO 00/37504, The sequences shown are incorporated herein by reference.

  The specific use of these antibodies to treat various cancers is discussed in US patent application Ser. No. 10 / 153,382, currently published as US Patent Application Publication No. 2003/0086930. The entirety of which is incorporated by reference as if set forth herein.

  Features of human anti-CTLA4 antibodies useful in the methods of the invention are discussed extensively, for example, in US Pat. No. 6,682,736, including but not limited to 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, 12.9.1.1, CP-675,206 and antibodies having the amino acid sequence of antibodies such as ipilimumab. The present invention also relates to antibodies comprising the heavy and light chain CDR amino acid sequences of these antibodies and methods comprising antibodies comprising changes in the CDR regions, as described in the applications and patents cited above. Also related. The invention also relates to antibodies comprising the heavy and light chain variable regions of those antibodies. In other embodiments, the antibody is 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 the total length of the heavy and light chains of ipilimumab, the variable region, or Selected from an antibody comprising the amino acid sequence of a CDR.

  Although the anti-CTLA4 antibodies discussed above herein may be preferred, one of ordinary skill in the art, based on the disclosure provided herein, will encompass a variety of anti-CTLA4 antibodies, and these specifics It will be understood that the present invention is not limited to these antibodies. More specifically, human antibodies are preferred, but the present invention is in no way limited to human antibodies; rather, the present invention encompasses useful antibodies regardless of species origin, especially chimeric antibodies. , Humanized antibodies, and / or primatized antibodies. Also, the antibodies exemplified herein were obtained using transgenic mammals, such as mice containing a human immune repertoire, but those of ordinary skill in the art, based on the disclosure provided herein, It will be appreciated that the invention is not limited to antibodies produced by this method or any other specific method. Instead, the present invention will be developed in the future to produce, but is not limited to, methods known in the art (eg, screening phage display libraries, etc.) or anti-CTLA4 antibodies of the invention. Including anti-CTLA4 antibodies produced by any method, including methods. Based on this specification and the broad disclosure provided, for example, in US Pat. No. 6,682,736 to Hanson et al. And US Patent Application Publication No. 2002/0088014, those skilled in the art will disclose herein. Using the novel methods described, antibodies useful for the treatment of prostate cancer in combination with hormonal therapeutic agents can be readily generated and identified.

  The present invention is made using a transgenic non-human mammal, XenoMouse ™ (Abgenix, Inc., Fremont, Calif.) As disclosed in US Pat. No. 6,682,736 to Hanson et al. Includes human antibodies.

  Another transgenic mouse system for making “human” antibodies is called “HuMAb-Mouse ™” (Medarex, Princeton, NJ), a targeted mutation that inactivates endogenous mu and kappa chain loci. Along with mutations (Lonberg et al., Nature 368: 856-859 (1994) and US Pat. No. 5,770,429), unrearranged human heavy (μ and γ) and kappa light chain immunoglobulins Contains the minilocus of the human immunoglobulin gene that encodes the sequence.

  However, the present invention is not limited thereto, for example, see Tomizuka et al., Proc Natl Acad Sci USA 97: 722 (2000); Kuroiwa et al., Nature Biotechnol 18: 1086 (2000); Mikayama et al. Kirin TC Mouse ™ as described in 2004/0120948 (Kirin Brewery, Tokyo, Japan); and the above HuMAb-Mouse ™ (Medarex, Princeton, NJ) and XenoMouse ™ (Abgenix, Inc.) Inc., Fremont, Calif.) Human anti-CTLA4 antibodies made using any transgenic mammal are used. Thus, the present invention encompasses the use of anti-CTLA4 antibodies made using any transgenic animal or other non-human animal.

  In other embodiments, the antibodies used in the methods of the invention are “humanized” rather than fully human. Specifically, murine antibodies or antibodies from other species can be “humanized” or “primatized” using techniques well known in the art. See, for example, Winter and Harris, Immunol. Today 14: 43-46 (1993), Wright et al., Crit. Reviews in Immunol. 12: 125-168 (1992), Cabilly et al., U.S. Patent No. 4,816,567, and Mage and Lamoyi, "Monoclonal Antibody Production Technologies and Applications", pages 79-97, Marcel Inc. , New York, New York (1987). Thus, a humanized chimeric antibody, an anti-CTLA4 antibody derived from any species (for example, a single antibody obtained from a camelid as described in US Pat. Nos. 5,759,808 and 6,765,087 of Castellman and Hamers Novel methods disclosed herein can be performed using any human antibody in combination with a therapeutic agent, including chain antibodies).

  As will be understood based on the disclosure provided herein, antibodies used in the present invention can be obtained from transgenic non-human mammals and hybridomas derived therefrom, but in cell lines other than hybridomas. Can also be expressed.

  Mammalian cell lines that can be used as hosts for expression are well known in the art and include, but are not limited to, Chinese hamster ovary (CHO) cells, NS0, Sp2, HEK, HeLa cells, pup hamster kidney (BHK). There are a number of immortalized cell lines available from the American Standard Strains Conservation Organization (ATCC), including cells, monkey kidney cells (COS), and human hepatocellular carcinoma cells (eg, Hep G2). Non-human prokaryotic and eukaryotic cells can also be used, including bacterial, yeast, insect, and plant cells.

  Nucleic acid molecules encoding anti-CTLA4 antibodies, expression vectors containing the nucleic acid molecules can be used for transfection of suitable mammalian, plant, bacterial or yeast host cells. Transformation may be by any known method for introducing a polynucleotide into a host cell. Methods for introducing 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, (multiple) into liposomes. Polynucleotide encapsulation) and direct microinjection of DNA into the nucleus. In addition, nucleic acid molecules can be introduced into mammalian cells by viral vectors. Methods for transforming plant cells are well known in the art, including, for example, Agrobacterium-mediated transfection, particle gun transformation, direct injection, electroporation and viral transformation. Methods for transforming bacteria and yeast cells are also well known in the art.

  A DNA particle gun can also be used to deliver the expression vector to the expression system, where the plasmid is precipitated onto microscopic particles, preferably gold particles, and the particles are fired into the target cell or expression system. DNA particle gun technology is well known in the art, and devices such as “gene guns” can be used in cells (eg, Helios Gene Gun, Bio-Rad Labs., Hercules, Calif.) And in the skin (PMED Device, PowderMed Ltd). , UK Oxford) is commercially available for delivery of microparticles.

  For example, but not limited to: Sambrook and Russell, “Molecular Cloning, A Laboratory Approach”, Cold Spring Harbor Press, Cold Spring Harbor, New York, Pros in, A variety of expression systems can be used, as is well known in the art, such as those described in New York State (2002). Among these expression systems, among others, there is a system based on dihydrofolate reductase (DHFR). Glutamine synthase expression systems are discussed in whole or in part in relation to European Patent Nos. 0216846B1, 0256605B1, and 0323997B1, and European Patent Application No. EP89303964. In one embodiment, the antibodies used are made in NS0 cells using the glutamine synthetase system (GS-NS0). In other embodiments, antibodies are made using the DHFR system in CHO cells. Both systems are well known in the art and are described, inter alia, in Barnes et al., Biotech & Bioengineering 73: 261-270 (2001), and references cited therein.

  Site-directed mutagenesis of the antibody CH2 domain that eliminates glycosylation may be preferred to prevent changes in immunogenicity, pharmacokinetics, and / or effector function resulting from non-human glycosylation. In addition, enzymatic methods (see, eg, Thotkura et al., Meth. Enzymol. 138: 350 (1987)) and / or chemical methods (eg, Hakimudin et al., Arch. Biochem. Biophys. 259: 52 (1987)). The antibody can be deglycosylated.

  Furthermore, the present invention encompasses the use of anti-CTLA4 antibodies that contain altered glycosylation patterns. One of ordinary skill in the art, based on the disclosure provided herein, will be able to include additional glycosylation sites, include fewer glycosylation sites, or include different glycosylation sites compared to naturally occurring antibodies. It will be appreciated that CTLA4 antibodies can be modified. Such modifications are described, for example, in US Patent Application Publication Nos. 2003/0207336 and 2003/0157108, and International Patent Publications WO01 / 81405 and 00/24893.

  Furthermore, the present invention encompasses the use of anti-CTLA4 antibodies that, if present, are independent of the glycoform present on the antibody. In addition, methods for extensive reconstruction of glycoforms present on glycoproteins are well known in the art, including, for example, International Patent Publications WO03 / 031464, WO98 / 58964, and WO99 / 22764, and US Patents. Nos. 2004/0063911, 2004/0132640, 2004/0142856, 2004/0072290, and Umana et al. US Pat. No. 6,602,684.

  Further, the invention is not limited thereto, for example, U.S. Patent Application Publication Nos. 2003/0207346 and 2004/0132640, and U.S. Pat. Nos. 4,640,835, 4,496,689, 301,144, 4,670,417, 4,791,192, 4,179,337, various non-proteinaceous polymers such as polyethylene glycol, polypropylene glycol Or the use of anti-CTLA4 antibodies with any covalent and non-covalent modifications known in the art, including the binding of one of the polyoxyalkylenes to the polypeptide.

  Furthermore, the present invention encompasses the use of an anti-CTLA4 antibody comprising a human serum albumin polypeptide or fragment thereof, or a chimeric protein of an antigen binding portion thereof, for example. Whether the chimeric protein is made using recombinant methods, for example by cloning a chimeric nucleic acid encoding the chimeric protein, or made by chemical conjugation of two peptide moieties, one skilled in the art After mastering the teachings provided, such chimeric proteins are well known in the art and the desired biological properties such as, but not limited to, increased stability and increased serum half-life for the antibodies of the present invention. It will therefore be appreciated that such molecules are included herein.

  The antibodies produced for use in the present invention need not initially have a particular desired isotype. Rather, the antibody produced may have any isotype, which can then be isotype switched using conventional techniques. This technique includes direct recombination techniques (see, eg, US Pat. No. 4,816,397) and cell-cell fusion techniques (see, eg, US Pat. No. 5,916,771). is there.

  For various therapeutic uses, effector functions of the antibodies of the invention can be altered by performing an isotype switch to IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM. In addition, dependence on complement for cell killing can be avoided, for example, through the use of bispecific antibodies, immunotoxins, or radiolabels.

  Antibodies 4.1.1, 4.13.1 and 11.2.1 (CP-675,206) are IgG2 antibodies, the sequence of the variable region of the antibody is described herein (FIGS. 1-3), and As provided in the applications and patents referenced and incorporated herein, the full-length sequences of these antibodies, as well as SEQ ID NOs: 1-36, as discussed more fully elsewhere herein It is understood that the use of any antibody comprising the sequence shown below and further comprising any constant region, regardless of isotype, is encompassed herein. Similarly, any antibody comprising the full-length sequence of ipilimumab, or any portion thereof comprising a sequence encoding the antigen-binding portion of ipilimumab can be used in accordance with the methods of the invention.

  Accordingly, those skilled in the art will readily understand that, after having learned the teachings provided herein, the anti-CTLA4 antibody-therapeutic agent combinations of the present invention can include a wide range of anti-CTLA4 antibodies. Let's go.

  Furthermore, one of ordinary skill in the art, based on the disclosure provided in the present invention, is not limited to administration of a single antibody alone; rather, the present invention employs at least one anti-CTLA4 in combination with a therapeutic agent. It will be understood to include the administration of one of the antibodies, eg 4.1.1, 4.13.1, or 11.2.1 (CP-675,206). Furthermore, 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.

IV. Therapeutic Agents The present invention relates to a combination of anti-CTLA4 antibody and at least one therapeutic agent, which further agents and / or treatment modalities for treating cancer, such as chemotherapy, surgery, radiation therapy, transplantation, etc. And can be used in combination. That is, but not limited to, growth factor inhibitors, biological response modifiers, alkylating agents, intercalating antibiotics, vinca alkaloids, immunomodulators, taxanes, platinum compounds, signal transduction inhibitors, but not limited to lasophor Additional chemotherapy can be given to the patient using known agents such as selective estrogen receptor modulators (SERMs) such as xifene and angiogenesis inhibitors.

  Co-administration of antibody and additional therapeutic agent (combination therapy) comprises administration of a pharmaceutical composition comprising both an anti-CTLA4 antibody and one or more additional therapeutic agents, and one comprises an anti-CTLA4 antibody, Others include the administration of two or more separate pharmaceutical compositions comprising additional therapeutic agent (s). Furthermore, co-administration or combination (joint) therapy generally means that the antibody and the additional therapeutic agent are administered simultaneously with each other, but it also administers the individual components of the treatment simultaneously, sequentially or separately. Is also included. It is further understood that when the antibody is administered intravenously and the anticancer agent is administered orally (eg, imatinib mesylate, gemcitabine, capecitabine, temozolomide, etc.), preferably the combination is administered as two separate pharmaceutical compositions. .

  There are many therapeutic agents, for example, among others, US Patent Application Publication Nos. 2004/0005318, 2003/0086930, 2002/0086014, all of which are incorporated herein by reference, And in International Publication WO 03/086459. Such therapeutic agents include, but are not limited to, topoisomerase I inhibitors; other antibodies (rituximab, bevacizumab, trastuzumab, anti-IGF1R antibodies [eg CP-751, 871], anti-CD40, among others. Chemotherapeutic agents such as, but not limited to, imatinib (GLEEVEC), SU11248 (SUTENT; sunitinib), SU12662, SU14813, BAY 43-9006, AG-013736 (axitinib) Toll-like receptor agonists (eg, TLR-9 agonists; but not limited to PF03512676 or CPG-7909, also referred to as PROMUNE), and other immunomodulators such as indoleamine 2,3 Immunomodulators, including dioxygenase (IDO) inhibitors; selective estrogen receptor modulators (SERM; eg, lasofoxifene); taxanes; vinca alkaloids; temozolomide; angiogenesis inhibitors; EGFR inhibitors; Agents; erb2 receptor inhibitors; antiproliferative agents (eg, farnesyl protein transferase inhibitors and αvβ3 inhibitors, αvβ5 inhibitors, p53 inhibitors, etc.); immunomodulators; biological response modulators; cytokines; tumor vaccines Tumor-specific antigens; heat shock protein-based tumor vaccines; dendritic cell therapy and stem cell therapy; alkylating agents; folic acid antagonists; pyrimidine antagonists; anthracycline antibiotics; platinum compounds; CD25, PD 1, B7-H3,4-1BB, OX40, ICOS, CD30, HLA-DR, MHCII, and LFA), and there are antibodies thereto.

  In one embodiment, the methods of the invention can be further combined with transplantation, eg, stem cell transplantation, to provide a therapeutic benefit to patients with breast cancer. Stem cell transplantation can be performed according to methods known in the art, which can be allogeneic or autologous stem cell transplantation. Furthermore, one of ordinary skill in the art will understand that, based on the disclosure provided herein, transplantation includes adoptive transfer of lymphocytes obtained from an autologous or HLA-matched donor. If the method involves stem cell transplantation, the first administration of the antibody-AI therapeutic combination can be performed after the mammalian immune system has recovered from the transplant, eg, 1-12 months after transplantation. In certain embodiments, the first administration is performed 1-3 months after transplantation, or 1-4 months. Methods of transplantation include Appelbaum, “Harrison's Principles of Internal Medicine”, Chapter 14, Braunwald et al., 15th Edition, McGraw-Hill Professional (2001), incorporated herein by reference. It is described in many technical books.

  As pointed out hereinbefore, there are a number of chemotherapeutic agents currently available for the treatment of tumors suitable for use in the combination therapy of the present invention. For example, alkylating agents are a class of drugs that alkylate DNA and restrict strands from being unwound and replicated. A preferred alkylating agent for use in the process of the present invention is cyclophosphamide (CYTOXAN). In one embodiment, CP-675,206 is administered with a low dose cyclophosphamide. Without being bound to a particular theory, this may mediate the removal of Treg at such doses, and it appears that CTLA4 blockade does not affect Treg, resulting in these two This is because the anti-tumor mechanism may have a synergistic therapeutic effect.

  Folate antagonists bind to dihydrofolate reductase (DHFR) and interfere with pyrimidine (thymidine) synthesis. Methotrexate and pemetrexed (ALIMTA) are folic acid antagonists suitable for use in the methods of the invention. In addition to DHFR, pemetrexed also inhibits two other folate-dependent enzymes involved in thymidine synthesis, thymidine synthase and glycinamide ribonucleotide formyltransferase.

  Pyrimidine antagonists inhibit enzymes involved in pyrimidine synthesis. As a pyrimidine analog, it also interferes 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), 5′-deoxy-5-fluorouridine which is converted to 5-FU enzymatically in vivo. (5'-FDUR) prodrug; and gemcitabine (GEMZAR).

  Anthracycline antibiotics inhibit DNA from being unwound by insertion 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 in the present invention include doxorubicin and epirubicin.

  The platinum compound exerts its antitumor effect by insertion between DNA strands and insertion within the DNA strand, and inhibits DNA from being unwound. Platinum compounds useful in the methods of the present invention include cisplatin (PLATINOL), oxaliplatin (ELOXATIN), and carboplatin (PARAPLATIN).

  Taxanes promote microtubule assembly while inhibiting their degradation to tubulin, thereby blocking the cell's ability to degrade the spindle during mitosis. It has shown significant activity against a number of solid cancers as a single agent therapy and in combination with other chemotherapeutic agents. One embodiment of the combination therapy of the invention involves the use of one or more taxanes in combination with an IGF-1R antibody. Taxanes suitable for use in combination with an IGF-1R antibody include docetaxel (TAXOTERE) and paclitaxel (TAXOL).

  Taxane derivatives that may be active in cells resistant to doxorubicin, vinblastine, paclitaxel, docetaxel and the like include XRP-9981 (Sanofi Aventis), which is encompassed by the present invention.

  Vinca alkaloids, like taxanes, are “spindle toxins” that act on the microtubules that form the spindle. It inhibits mitosis by interfering with microtubule assembly and preventing the formation of spindles. Vinca alkaloids include vindesine (ELDISINE), vinblastine sulfate (VELBAN), vincristine sulfate (ONCOVIN) and vinorelbine tartrate (NAVELBINE). A preferred vinca alkaloid for use in the method of the present invention is vinorelbine.

  BMS-247550 (ixabepilone) promotes tubulin polymerization and microtubule stabilization, thereby causing cells to arrest in the G2M phase and inducing apoptosis of tumor cells. This agent is active against taxane resistant cells.

  Analogs of rapamycin that bind to and inhibit the mammalian rapamycin target (mTOR) are also useful, among others, CCI-779 (temsirolimus; Wyeth) and RAD-001 (everolimus, CERTICAN; Novartis).

  Camptothecin analogs act through inhibition of topoisomerase I, an enzyme important for DNA replication and packing. Topoisomerase I levels are higher in tumor cells than in normal tissues. A camptothecin analog useful in the methods of the present invention is irinotecan (CAMPTOSAR). Topoisomerase I inhibitors useful in embodiments of the present invention include 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan ( 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 present invention, including camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof .

  A particularly preferred topoisomerase I inhibitor is irinotecan (CAMPTOSAR).

  Topoisomerase II inhibitors useful in the combination embodiments of the present invention include aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galaruvicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, and zeradixane.

  Particularly useful topoisomerase II inhibitors include epirubicin (Ellence), doxorubicin, daunorubicin, idarubicin and etoposide.

  Alkylating agents that can be used in embodiments of the present invention include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apadicone, brostallicin (Brostalicin), bendamustine, busulfan, carbocon, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, maphosphamide, mechloretamine, melphalan, mitoblonitol, mitoctomytomycin Santron, nimustine, ranimustine, temozolomide, thiotepa, and cisplatin, carboplatin (PARAPLA) IN), Eputapurachin, lobaplatin, nedaplatin, oxaliplatin (ELOXATIN, Sanofi), streptozocin, platinum-coordinated alkylating compounds such as satraplatin, as well as combinations thereof.

  Antimetabolites that can be used in combination therapy with a CTLA4 antibody, optionally with one or more other agents, include, but are not limited to, dihydrofolate reductase inhibitors (methotrexate and NeuTrexin (trimethyl glucuronate). Trexate)), purine antagonists (6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clarar), fludarabine, nelarabine, raltitrexed, etc.), pyrimidine antagonists (5-fluorouracil (5-FU), Pemetrexed disodium (Alimta, LY231514, MTA), capecitabine (Xeloda), cytosine arabinoside, gemcitabine (Gemzar, Eli Lilly), Tegafu (Including UFT Orzel or Uforal, tegafur, gimestat, and otostat TS-1 combination), doxyfluridine, carmofur, cytarabine (including ocphosate, phosphate, stearate, sustained-release and liposome types), Enocitabine, 5-azacytidine (Vidaza), decitabine, ethinyl cytidine, etc.) and eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine (triapine), trimethrexate, and N- (5- [N- (3 , 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino] -2-thenoyl) -L-glutamic acid and the like are disclosed in European Patent Application No. 239362. Other antimetabolites, such as one of the preferred antimetabolites, as well as combinations thereof.

  In other embodiments, the anti-cancer agent is a poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor such as AG-014699, ABT-472, INO-1001, KU-0687, or GPI 18180.

  Microtubule inhibitors that can be used in combination therapy with a CTLA4 antibody, optionally with one or more other agents, include, but are not limited to, ABI-007, albendazole, betabulin, There are CPH-82, EPO 906 (Novartis), Discodermolide (XAA-296), Vinfunine and ZD-6126 (AstraZeneca).

  Antibiotics that may be used in combination therapy with a CTLA4 antibody, optionally with one or more other agents, include, but are not limited to, actinomycin D, bleomycin, mitomycin C, neocartinostatin ( Zinostatin), peplomycin insertion antibiotics and combinations thereof.

  Plant-derived antitumor substances (also known as spindle inhibitors) that can be used in combination therapy with CP-675,206 include, but are not limited to, mitotic inhibitors such as vinblastine, vincristine, vindesine. , Vinorelbine (NAVELBINE), docetaxel (TAXOTERE), ortataxel (Ortataxel), paclitaxel (including Taxoprexin, which is a DHA / paclitaxel conjugate) and combinations thereof.

  Platinum coordination compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin (ELOXATIN), satraplatin (JM-126), and combinations thereof.

  Other agents include alitretinoin, l-asparaginase, AVE-8062 (Aventis), calcitriol (vitamin D derivative), canfosfamide (Telcyta, TLK-286), Cotara (131 I chTNT 1 / b), DMXAA (Antisoma), Exisulind, ibandronic acid, miltefosine, NBI-3001 (IL-4), pegaspargase, RSR13 (efaproxiral), Targretin (bexarotene), tazarotene (vitamin A derivative), tesmilifene ( DPPE), Theratope, Tretinoin, Trizaone (Tirapazamine), Xcyrin (Motexafingadolinium (motexaf) in gadoolinium)) and Xyotax (polyglutamic acid-added paclitaxel), and combinations thereof.

  In other embodiments of the invention, statins can be used in combination with CP-675,206. Statins (HMG-CoA reductase inhibitors) are atorvastatin (Lipitor, Pfizer Inc.), pravastatin (Pravachol, Bristrol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, McForc, M Statins (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovastatin and Niacin (Advicor, Kos Pharmaceuticals), derivatives and combinations thereof can be selected.

  In a preferred embodiment, the statin is selected from the group consisting of atorvastatin and lovastatin, derivatives and combinations thereof.

  Other agents useful as anticancer agents include CADUET, Lipitor and torcetrabib.

  In certain embodiments of the invention, the methods described above can be performed, including vaccines that use autologous or allogeneic tumor cells, eg, 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. et al. 2000, ASCO Educational Book Spring: 730-738 (Restifo, N. and Sznol, M., 1997, Cancer: Principles and Practice of Oncology, pages 3023-3043, 5th edition, DeVit et al. (See also (1997)). Cellular vaccines have been shown to be particularly effective when transducing tumor cells to express GM-CSF, a potent activator of antigen presentation upon tumor vaccination (Dranoff et al., ( 1993) Proc. Natl. Acad. Sci USA 90 (8): 3539-43).

  A number of tumor-specific antigens have been identified so far. The study of gene expression and large gene expression patterns in various tumors has led to the definition of so-called tumor-specific antigens (Rosenberg, SA, Immunity 10: 281-287 (1999)). In many cases, the tumor-specific antigen is a differentiation antigen expressed in the tumor and in the original cell from which the tumor originated, such as the melanocyte antigen gp100, MAGE antigen, Trp-2. Tumor antigens are also required for the synthesis of chromosomal telomeres and may include protein telomerases that are expressed in more than 85% human cancers but only in a limited number of somatic tissues (Kim, N et al., Science 266: 2011-2013 (1994)). These somatic tissues may be protected from immune attack by various means. More importantly, many of these antigens may be shown to be targets of tumor-specific T cells found in the host, and such tumor-specific antigens are used in combination with anti-CTLA4 antibodies. Thus, cancer can be treated by stimulating an anti-tumor response in the host. More specifically, CTLA4 inhibition can make these otherwise non-immunogenic proteins immunogenic, which mediates an immune response against tumor cells that express them. The That is, these proteins are usually considered self-antigens by the immune system and thus generate immune tolerance, but such tolerance can be overcome by anti-CTLA4 antibodies.

  Tumor-specific antigens also alter the sequence of the protein or convert the fusion protein between two unrelated sequences (ie, bcr-abl in the CML Philadelphia chromosomal mutation), or an idiotype from a B cell tumor. It may also be a “neoantigen” that is expressed in cancer cells due to the somatic mutation it creates. Other tumor vaccines may include proteins from viruses associated with human cancer, such as human papilloma virus (HPV), hepatitis virus (HBV and HCV), and Kaposi herpes sarcoma virus (KHSV). Regardless of the source of the tumor-specific antigen, if it is expressed by tumor cells, co-administration of the antigen with an anti-CTLA4 antibody can expose the tumor cells to an immune attack, thereby providing a therapeutic effect. It is.

  Another type of tumor-specific antigen that can be used in conjunction with CTLA antibody administration is purified heat shock protein (HSP) isolated from tumor tissue. This heat shock protein contains a fragment of a protein derived from tumor cells and is very effective in the delivery of antigen presenting cells to elicit tumor immunity (Suot, R and Srivastava, P, Science 269: 1585-1588). (1995); Tamura, Y. et al., Science 278: 117-120 (1997)). Thus, administration of anti-CTLA4 antibody in combination with tumor HSP can provide significant benefits by mediating an immune response against the tumor. Among the HSP-based tumor vaccines and methods of making them are, for example, ONCOPHAGE (HSPPC-96) and AG-858 (HSPPC-70), both from Antigenics (Lexington, Mass.).

  Another therapeutic agent that can be used in combination with an anti-CTLA4 antibody is dendritic cells (DC). DCs are powerful antigen presenting cells that can be used to stimulate antigen-specific responses. DCs can be generated ex vivo, into which various protein and peptide antigens and tumor cell extracts can be introduced (Nestle, F. et al., Nature Medicine 4: 328-332 (1998)). When introducing tumor cell extracts into DCs, it is not necessary to reveal the exact nature of the tumor antigen, rather, DC cells process the tumor extract and present the antigen (s) in the context of MHC. . Thus, there is no need to elucidate the nature of the antigen, and the ability of the DC to present it can be utilized. DCs can be transduced by genetic means to express the desired tumor antigen as well. DCs can also be fused directly with tumor cells for immunization purposes (Kugler, A. et al., Nature Medicine 6: 332-336 (2000)). As a method of tumor vaccination, DC immunization can be effectively combined with anti-CTLA antibodies to mediate a stronger anti-tumor response. Oh et al., Cancer Res. 64: 2610-2618 (2004) (TARP epitopes and breast cancer); Kontani et al., Int J Molec Med 12: 493-502 (2003) (dendritic cell vaccine targeting MUC1 mucin); Holmberg and Sandmaier, Expert See also Rev Vaccines 3: 269-277 (2004) (immunization of breast or ovarian cancer).

  As suggested by the data disclosed herein, co-administration of anti-CTLA4 antibodies can enhance the immune response to vaccine-specific antigens. Accordingly, the present invention includes a method of treating cancer comprising administering a therapeutically effective amount of an anti-CTLA4 antibody and a therapeutically effective amount of at least one therapeutic agent to a patient in need thereof. Including, the agent includes a vaccine and / or antigen, or a combination of antigens, or cells that present the antigen and / or express a cytokine, such as GM-CSF.

  That is, useful vaccines include but are not limited to breast cancer associated antigens (eg, HER-2 / neu, mammaglobin, prostate cancer and breast cancer associated proteins [TARP], MUC1, CEA, sialyl-Tn and other carbohydrate antigens). , Other tumor cancer-associated antigens (eg, p53, telomerase), those consisting of anti-idiotype antibodies such as 11D10, and vaccines containing GM-CSF (eg, GVAX, Cell Genesys, Inc., Lapuleucel-T [APC8024]) And Sipleucel-T [APC8015], Dendreon Corp .; and TVAX, Geron Corp.), DNA and cell based vaccines, dendritic cell vaccines (Banchereau and Pallacka). Nature Revs. Immunol.5: 296-306 (2005)), recombinant virus (eg, vaccinia virus) vaccines, and heat shock protein (HSP) vaccines (eg, vitespen [ONCOPAGE]). , Antigens Inc.).

  In one embodiment, the invention encompasses a combination of CP-675,206 and a tumor antigen. Tumor antigens or tumor associated antigens (TAA) include, for example, cancer-germ cell (CG) antigens (MAGE, NY-ESO-1), mutant antigens (MUM-1, p53, CDK-4), overexpressed self Antigen (p53, HER2 / NEU), viral antigen (from papilloma virus, Epstein Barr virus), tumor protein derived from non-primary open reading frame mRNA sequence (NY-ESO1, LAGE1), melan A, MART-1, MAGE -1, MAGE-3, BAGE, GAGE-1, GAGE-2, tyrosinase, gp100, gp75, HER-2 / neu, c-erb-B2, CEA, PSA, MUC-1, CA-125, sialyl-Tn (STn), STn-KLH (THERATOPE, Biomira Inc.), TAG- 2, KSA (17-1A), PSMA, p53 (point mutation type and / or overexpression type), RAS (point mutation type), EGF-R, VEGF, GD2, GM2, GD3, anti-Id, CD20, There are CD19, CD22, CD36, abnormal class II, B1, CD25 30 (IL-2R) (anti-TAC), or HPV. TAA is described in, for example, Palena et al., Adv. Cancer Res. 95: 115-145 (2006) and other art-recognized books recognized in the art, including the use of gp100 from non-human species, such as mouse gp100, to increase or enhance anti-tumor responses .

  In one embodiment, the TAA comprises at least one feature that is likely to be associated with the development or enhancement of an anti-tumor immune response. Such characteristics may include, but are not limited to, dominance, specificity, immunogenicity, and a need for cell survival or proliferation. More specifically, dominance means that the antigen is present in most patients with a particular type of cancer. In other embodiments, the more cancer cell types that express an antigen compared to the expression of the antigen by normal cells, the more desirable the dominance. In still other embodiments, the TAA has significantly greater TAA expression on the cancer cell compared to the expression level of TAA on the same cell except that it is not cancer, more preferably the TAA is on normal cells. Is not detectable to the extent that it is detectable, but is specific for cancer cells in that it is expressed on most if not all cancer cells in a patient. Most preferably, TAA is unique to tumor cells and is not expressed in normal cells.

  In yet other embodiments, the TAA is immunogenic, for example, it induces a detectable immune response in tumor cells. More specifically, TAA is more preferable as the response scale is larger. Much preferably, TAA induces, increases and / or prolongs the cellular immune response.

  In other embodiments, TAA is essential for cell growth or survival. That is, TAA is required for tumor cells to survive, grow and / or proliferate. Much preferably, TAA is essential for tumor cells so that affecting or inhibiting the biological activity of TAA prevents or inhibits cell survival or proliferation. Much preferably, TAA is essential, so that inhibiting or reducing the biological activity of the antigen will result in tumor cell variants that do not express the antigen, or mutant antigens that are not affected by the anti-tumor immune response to the original TAA Generation or selection of mutant cells expressing is inhibited. That is, when an immune response against an antigen is induced, cell survival is prevented or inhibited, and as a result, mutant antigens that avoid the immune response are not selected.

  In one embodiment, 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), whereby the immune response to the vaccine is increased. Induction, enhancement and / or prolongation, thereby providing a therapeutic benefit to the patient. In one aspect, at least one additional treatment such as, but not limited to, a chemotherapeutic agent, an immunomodulatory agent (TLR-9 agonist), an immunopotentiating antibody (eg, an agonist anti-CD40 antibody), among many additional agents. CP-675,206 can be administered with the active agent.

  In other embodiments, the vaccine is administered prior to or after administration of the antibody-therapeutic agent combination, and when chemotherapy is part of the therapy, the vaccine is administered prior to chemotherapy. Can do. In certain embodiments, the antibody-therapeutic agent combinations of the invention can also be administered prior to chemotherapy. In yet other embodiments, the treatment can be combined with stem cell transplantation. That is, the antibody-chemotherapeutic agent combination can be administered before and after stem cell transplantation. The vaccine can also be administered before and after stem cell transplantation, and in certain embodiments, simultaneously with the antibody.

  Stem cell transplantation can be performed according to methods known in the art. Some such methods are described in Appelbaum, “Harrison's Principles of Internal Medicine”, Chapter 14, Braunwald et al., 15th Edition, McGraw-Hill Professional (2001), incorporated herein by reference. It is described in. Accordingly, the method of the present invention relates to the treatment of cancer in a mammal that has undergone a stem cell transplant, the method comprising administering to a mammal an amount of a human anti-CTLA4 antibody in combination with a therapeutic agent, comprising: The combination is effective in treating cancer further combined with stem cell transplantation.

  If the method involves stem cell transplantation, the antibody-therapeutic agent combination can be administered for the first time after the mammalian immune system has recovered from the transplant, eg, 1-12 months after the transplant. In certain embodiments, the first administration is performed 1-3 months after transplantation, or 1-4 months. The patient may have undergone stem cell transplantation and preliminary treatment (s).

  In particular, when a standard cancer treatment such as chemotherapy is combined with an anti-CTLA4 antibody, the amount of chemotherapeutic agent administered can be reduced (Mokyr, M. et al., Cancer Research 58: 5301-5304). 1998)). This is because the combination of anti-CTLA4 antibody and chemotherapy mediates cell death resulting from the cytotoxic effects of most chemotherapeutic compounds. Such cell death is likely to increase the level of tumor-specific antigens in the antigen presentation pathway, and anti-CTLA4 antibodies mediate an increased immune response thereto. Other combination therapies that can enhance immune responses through release of tumor antigens through cell death in synergy with anti-CTLA4 are, among other things, radiation, surgery, and hormone removal. Each of these protocols, and other protocols described elsewhere herein, provides a source of tumor antigens in the host. Similarly, angiogenesis and signal inhibitors can also cause tumor cell death if inhibition of angiogenesis or signal transduction, thereby supplying tumor antigens to the host antigen presentation pathway, thus anti-CTLA4 antibodies Can be used in combination to increase the immune response to the tumor. Thus, the combination therapy disclosed herein can increase the source of tumor-specific antigens, thereby increasing the immune response to the tumor, thereby providing a therapeutic benefit to the patient.

  The present invention provides an anti-CTLA4 antibody and an agent capable of inhibiting an EGFR (epidermal growth factor receptor) response (eg, an EGFR antibody, an EGF antibody, and a molecule that is an EGFR inhibitor) as described above; VEGF (vascular endothelial growth factor) inhibitors (eg, VEGF receptors and molecules that can inhibit VEGF); erbB2 receptor (HER2) inhibitors (eg, small molecules or antibodies that can bind to erbB2 receptors) And exemplary antibodies include a combination of at least one signaling inhibitor such as trastuzumab and HER dimerization inhibitor (HDI) is pertuzumab).

  EGFR inhibitors are described, for example, in International Patent Publications WO95 / 19970, WO98 / 14451, WO98 / 02434, and US Pat. No. 5,747,498, and such substances are described in the present specification as described herein. Can be used in the invention. EGFR inhibitors include, but are not limited to, monoclonal antibody C225, anti-EGFR 22 Mab (ImClone Systems Inc., New York, NY), and ABX-EGF (Abgenix Inc., Remont, Calif.), Compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex, Inc., Annedale, NJ), and OLX-103 (Merck & Co., Whitehouse GF, E), TP, TP-38) Fusion protein, EGF vaccine, anti-EGFR immunoliposome (Hermes Biosci nces Inc.), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc., Massachusetts Hopkinton) there is. These and other EGFR inhibitory agents can be used in the present invention in combination with anti-CTLA4 antibodies to treat a variety of cancers.

  Compounds directed at the inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) represent a relatively new class of anti-tumor agents useful in the methods of the invention. Many human cancers express EGFR family members on the cell surface. When a ligand binds to EGFR, it triggers a cascade of cellular responses that increases cell division, which includes other aspects of cancer development and progression, including angiogenesis, spread of metastasis, and inhibition of apoptosis. Affects aspects of EGFR-TK inhibitors are components 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), Alternatively, one of HER4 (also known as ErbB-4)) may be selectively targeted, or two or more of them may be targeted. EGFR-TK inhibitors suitable for use in the present invention include gefitinib (IRESSA), erlotinib (TARCEVA), CI-1033 (Pfizer), GW2016 (GlaxoSmithKline), EKB-569 (Wyeth), PKI-166 (Novartis). ), CP-724, 714 (Pfizer), CI-1033 (canertinib, Pfizer Inc), and BIBX-1382 (Boeringer-Ingelheim). Additional EGFR-TK inhibitors are described in US Pat. No. 6,890,924.

  VEGF inhibitors such as SU-5416, SU-6668, SU-11248, SU-12262, SU-14683 (Sugen / Pfizer), and AG-013736 (Pfizer) and CP-547,632 (Pfizer, NY) Can also be used in combination with an anti-CTLA4 antibody. VEGF inhibitors are, for example, international patent application PCT / IB99 / 00797 (filed on May 3, 1999), international patent publication WO 95/21613; WO 97/22596 (published June 26, 1997); WO 97/32856. (Published on September 12, 1997); WO 98/02437 and WO 98/02438 (both published on January 22, 1998); WO 98/50356; WO 98/54093 (published on December 3, 1998); WO 99 / 10349 (published March 4, 1999); WO 99/16755 (published April 8, 1999); WO 99/24440; WO 99/61422; US Pat. Nos. 5,792,783, 5,834 No. 504; No. 5,883,113; No. 5,886,020; No. 6,177,401; 6,235,764; 6,316,429; 6,395,734; 6,492,383; 6,534,524; and 6,653,308 ing. Other examples of specific VEGF inhibitors useful in the present invention include vandetanib (Zactima), sorafenib (Bayer / Onyx), AEE788 (Novartis), AZD-2171, VEGF Trap (Regeneron / Aventis), Batarinib (vatalinb) PTK-787, also known as ZK-222584; Novartis / Schering AG, described in US Pat. No. 6,258,812, MACUGEN (pegaptanib octasodium, NX-1838, EYE-001; Pfizer Inc./Gilead/ Eyetech), IM862 (Cytran Inc., Kirkland, WA); Neobastat, IMC-1C11 ImClone antibody, Bebashi Zumab (AVASTIN, Genentech, Inc., San Francisco, Calif.); Cetuximab (ERBITUX, ImClone); and Ribozyme (Boulder, Colorado); is there.

  ErbB2 receptor inhibitors such as GW-282974, GW-572016 (Lapatinib) (Glaxo Wellcome plc), and monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc., Woodland, TX), Mapatum C1 (HHS-E Inc. (TRAIL receptor 1 agonist)), trastuzumab (HERCEPTIN; Genentech, Inc., San Francisco, Calif.), Pertuzumab (OMNITARG; 2C4; Genentech, HER2 dimerization inhibitor (HDI)); TAK-165 (Takeda) ), GW-572016 (Lapatinib, GlaxoSmithKl) ne), peritinib (EKB-569, Wyeth), BMS-599626, PKI-166 (Novartis), dHER2 (HER2 vaccine, Corixa and GlaxoSmithKline), Osidem (IDM-1), APC8024D HER2 Anti-HER2 / neu bispecific antibody (Decof Cancer Center), B7. her2. IgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibody (University of Munich), mAB AR-209 (Aronex Pharmaceuticals Inc), and 2B-1 (Chiro CT4 In combination with antibodies, an effective combination therapy can be provided. Other erbB2 receptor inhibitors include, for example, International Patent Publication WO 95/19970 (published July 27, 1995); WO 97/13760 (published April 17, 1997); WO 98/02434 (January 1998) WO 98/02437 (published January 22, 1998); WO 99/35132 (published July 15, 1999); WO 99/35146 (published July 15, 1999); US patents 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 International Patent Publication WO 00/44728 (published August 3, 2000). ErbB2 receptor inhibitors useful in the present invention are also disclosed in US Pat. Nos. 6,465,449 and 6,284,764, and international applications, each of which is incorporated herein by reference in its entirety. It is also described in WO2001 / 98277. The erbB2 receptor inhibitor compounds and substances described in the aforementioned PCT applications, US patents, and US provisional applications, as well as other compounds and substances that inhibit erbB2 receptors, are combined with anti-CTLA4 antibodies in combination therapy according to the present invention. Can be used.

  Various other compounds, such as styrene derivatives, have also been shown to have tyrosine kinase inhibitory properties, and several tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. Other erbB2 inhibitors are listed in European Patent Publications EP566,226A1 (published on October 20, 1993), EP602,851A1 (filed on June 22,1994), EP635,507A1 (published on January 25, 1995). ), EP 635,498A1 (published on January 25, 1995), and EP520,722A1 (published on December 30, 1992). These publications refer to specific bicyclic derivatives, specifically quinazoline derivatives that have anticancer properties resulting from their tyrosine kinase inhibitory properties. WO 92/20642 (published November 26, 1992) also refers to certain bismono- and bicyclic aryl and heteroaryl compounds that are useful tyrosine kinase inhibitors in inhibiting abnormal cell growth. is there. WO96 / 16960 (published on June 6, 1996), WO96 / 09294 (published on March 6, 1996), WO97 / 30034 (published on August 21, 1997), WO98 / 02434 (January 1998) WO 98/02437 (published January 22, 1998) and WO 98/02438 (published January 22, 1998) are also substituted tyrosine kinase inhibitors useful for the same purpose. Reference is made to cyclic heteroaromatic derivatives. Other patent applications that refer to anti-cancer compounds are International Patent Applications WO 00/44728 (published on August 3, 2000), EP 1029853A1 (published on August 23, 2000), and WO 01/98277 (2001 12). All of which are hereby incorporated by reference in their entirety.

  BAY 43-9006 (Onyx Pharmaceuticals) is an inhibitor of both the RAF / MEK / ERK signaling pathway and the VEGFR-2 / PDGFR-β signaling cascade. RAF kinase is an enzyme in the RAS pathway, and mutations in the RAS gene are found in all human cancers, including 90% of pancreatic cancer, 50% of colon cancer and about 30% of small cell lung cancer (NSCLC). Related to about 20%, the specific RAF kinase BRAF has been shown to be mutated in about two thirds of melanoma and some colorectal cancer (CRC) and other solid cancers . Furthermore, VEGFR and PDGFR-β play an important role in angiogenesis, and thus inhibiting them reduces angiogenesis. Accordingly, the present invention encompasses administration of a combination comprising an anti-CTLA4 antibody and BAY 43-9006 for treating cancer.

  PDGFR inhibitors include, but are not limited to, International Patent Publication WO 01/40217, published on June 7, 2001, and International Patent Publication WO 2004/020431, 2004, the entire contents of which are incorporated for all purposes. Some are publicly disclosed on March 11th.

  Preferred PDGFR inhibitors include Pfizer's CP-673,451 and CP-868,596, and pharmaceutically acceptable salts thereof.

  TIE-2 inhibitors include International Patent Publication WO02 / 044156, published on June 6, 2002, WO03 / 066601, published on August 14, 2003, WO03 / 074515, published on September 12, 2003, There are benzimidazoles and pyridines of GlaxoSmithKline, including GW-697465A as described in WO 03/022852, published 20 March 2003 and described in WO 01/37835, published 31 May 2001. Other TIE-2 inhibitors include Regeneron biologics, such as those described in International Patent Publication WO 09/611269, published on April 18, 1996, Amgen AMG-386, International Patent Publication WO 09/955335. And Abbott pyrrolopyrimidines such as A-422885 and BSF-466895 described in WO09 / 918770, WO00 / 075139, WO00 / 027822, WO00 / 017203 and WO00 / 017202.

  The use of angiogenesis inhibitors in combination with anti-CTLA4 antibodies has been discussed previously elsewhere herein. In addition, angiogenesis inhibitors include, but are not limited to, bevacizumab (AVASTIN), a humanized antibody against VEGF. Bevacizumab can be used in combination with 5FU and is indicated as a first line treatment for patients with metastatic cancer of the colon or rectum. Agents that directly target angiogenic factors or their receptors are expected to be highly active in receptor-responsive hematologic malignancies by interfering with autocrine receptor signaling. Bevacizumab persistently neutralizes circulating VEGF and may be useful in the treatment of myelodysplastic syndrome (MDS), lymphoma, acute myeloid leukemia (AML), and solid cancer. Thus, combination therapy of anti-CTLA4 antibody and bevacizumab in combination with 5FU and additional chemotherapeutic agents to treat CRC and other malignancies is encompassed by the present invention.

  In another embodiment of the present invention, the anti-angiogenic agent is enzastaurine, midostaurin, perifosine, a staurosporine derivative (such as RO 318425, RO 317549, RO 318830 or RO 318220 (Roche)), teprenone (SELBEX) or UCN. A protein kinase Cβ such as -01 (Kyowa Hakko).

  Receptor tyrosine kinase inhibitors (RTKI) represent a class of synthetic small molecule inhibitors of angiogenic receptor signaling. The first receptor antagonist to enter clinical trials in hematologic malignancies is SU5416 (Sugen), which impairs ligand-induced VEGFR-1 and VEGFR-2 receptors and c-Kit autophosphorylation. SU5416 inhibits VEGF-induced clonogenic response in leukemic cell lines and promotes apoptosis of myeloblasts from AML patients. Other RTKIs are used in combination with anti-CTLA4 antibodies, including SU11248 (Sunitinib), SU12662, SU14813 (Pfizer Inc.), Batalanib (also known as PTK787 / ZK222584; Novartis), and AG-013736 (Pfizer). AML and other receptor-responsive hematologic malignancies can be treated. CP-675,206 can be used in combination with sunitinib (SU11248) among RTKIs. Accordingly, the present invention relates to anti-CTLA4 antibodies and, for example, SU-11248, SU-12626, SU-14613, AG-013736, and other angiogenesis and signaling inhibitors well known in the art or developed in the future. A combination of at least one anti-angiogenic agent and / or signaling inhibitor including the agent.

  As indicated above, the combination therapies of the invention include, but are not limited to, additional CTLA4 antibodies, different CTLA4 antibodies, and other agents that can also block CTLA4; farnesyl protein transferase inhibitors, and αvβ3 antibody VITAXIN Useful in treating abnormal cell proliferation or cancer, including other agents that can enhance anti-tumor immune responses, such as anti-proliferative agents such as αvβ3 inhibitors, αvβ5 inhibitors, p53 inhibitors, etc. Can be used with other agents.

  When the antibody of the present invention is administered in combination with other immunomodulators, the immunomodulators include, for example, dendritic cell activators such as CD40 ligand and anti-CD40 agonist antibodies, as well as enhancers for antigen presentation, T cell tropism And an enhancer of TGF-β (transforming growth factor β) or an inhibitor of tumor-related immunosuppressive factors such as IL-10. Preferred anti-CD40 agonist antibodies include but are not limited to antibodies 3.1.1, 3.1.1. H-A78T, 3.1.1H-A78T-V88A-V97A, 3.1.1L-L4M-L83V, 3.1.1H-A78T-V88A-V97A / 3.1.1L-L4M-L83V, 7. 1.2, 10.8.3, 15.1.1, 21.2.1, 21.4.1, 21.2.1, 22.1.1.1H-C109A, 23.5.1, 23. International patent application PCT /, including antibodies having heavy and light chain amino acid sequences of 25.1, 238.28.1, 233.28.1H-D16E, 23.29.1, and 24.2.1. US 02/36107, filed Nov. 8, 2002, currently published as International Patent Publication No. WO 03/040170, and U.S. Patent Application No. 10 / 292,088, filed Nov. 8, 2002, currently U.S. Patent Publication No. 2003 / 021110 It encompasses antibodies disclosed published as No..

  The treatment can also be used in combination with antibodies or other ligands that inhibit tumor growth by binding to IGF-1R (insulin-like growth factor 1 receptor). Specific IGF-1R antibodies that can be used in the present invention include international patent application PCT / US01 / 51113, filed December 20, 2001, published as international patent publication WO 02/053596, and international patent application PCT / IB 2004/002555, filed on Aug. 3, 2004, and published as International Patent Publication WO 2005/016967. Preferred anti-IGFR-1R antibodies are, for example, the heavy chains of antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3 and Includes antibodies having a light chain amino acid sequence.

  Ligands that inhibit signaling through IGF-1R also include small molecules and other ligands, including, inter alia, Somabert (PEGVISOMANT), a growth hormone analog that inhibits IGF-1 signaling. PEGVISOMANT can be combined with polyethylene glycol and used to specifically treat acromegaly. PEGVISOMANT can be co-administered with an anti-CTLA4 antibody to treat cancer in that the combination can inhibit tumor growth. Thus, PEGVISOMANT, like anti-IGF-1R antibodies, can be used in combination with anti-CTLA4 antibodies to treat cancer as disclosed herein.

Further exemplary therapeutic and / or prophylactic antibodies include, but are not limited to, SYNAGIS (MedImmune, MD), a humanized anti-respiratory syncytial virus (RSV) monoclonal antibody; a chimeric anti-TNFα monoclonal antibody REMICADE (Infliximab) (Centocor, PA); REOPRO (absiximab) (Centocor), an anti-glycoprotein IIb / IIIa receptor; ZENAPAX (Daclizumab) (Roche PharmaceuticalST, Switzerland), a humanized CD25 monoclonal antibody; Bevacizumab); matuzumab (Merck AG), nimotuzumab, panitumumab, EGFR inhibitory antibody (Amgen / Abgenix); ERB There is ITUX (cetuximab). Other examples are humanized anti-CD18 F (ab ′) ₂ (Genentech); humanized anti-CD18 F (ab ′) ₂ CDP860 (Celltech, UK); anti-HIV gp120 antibody PRO542 fused to CD4 ( Prostics / Genzyme Transgenes); OSTAVIR (Protein Design Lab / Novartis), which is a human anti-hepatitis B virus antibody; PROTOVIR (Protein Design Lab / Novartis), which is a humanized anti-CMV IgG1 antibody; ₂ ) MAK-195 (SEGARD) (Knoll Pharma / BASF); IC14 (ICOS Pharm), an anti-CD14 antibody; Humanized anti-VEGF IgG1 antibody (Gene) ntech); a murine anti-CA125 antibody, OVAREX (Altarex); a murine anti-17-IA cell surface antigen IgG2a antibody, PANORX (Glaxo SmithKline / Centocor); a murine 5 anti-idiotype (GD3 epitope) IgG antibody, BEC2 (ImClone) System); chimeric anti-EGFR IgG antibody IMC-C225 (ImClone System); humanized αVβ3 integrin antibody VITAXIN (Applied Molecular Evolution / MedImmune); humanized anti-CD52 IgG1 antibody CampeP03HL ); Smart M195 (Protein Des), a humanized anti-CD33 IgG antibody gn Lab / Kanebo); Rituximab, a chimeric anti-CD20 IgG1 antibody (RITUXAN) (Biogen IDEC / Genentech, Roche / Zettyaku); BEXAR (131-I-tositumomab); Belimumab (LymphoHStuMx); Genmab); R 1594 (Roche / Genentech); TRU-015 (Trubion Pharmaceuticals); Ocrelizumab (PRO 70769); LYMPHOCIDE (ImmunomedHsIDH anti-CD22 IgG antibody; (Protein Design Lab); Radiolabeled murine anti-HLA diagnosis Reagent antibody ONCOLYM (Lym-1) (Techniclone); human anti-IL8 antibody ABX-IL8 (Abgenix); humanized IgG1 antibody anti-CD11a (Genentech / Xoma); humanized anti-ICAM3 antibody ICM3 (ICOS Pharm); IDEC-114 (IDEC Pharm / Mitsubishi), a primatized anti-CD80 antibody; SGN14 (Seattle Genetics) of chimeric CD40 antibody; SGN40 (Seattle Genetics) of humanized anti-CD40 antibody; CHIR of antagonist CD40 antibody -12.12 (Chiron); ISF-154 (Ad-CD154, Tragen); tralizumab; ABI-793 (Nova) tis); IDEC-131 (IDEC / Eisai), a humanized CD40L antibody; IDEC-151 (IDEC), a primatized anti-CD4 antibody; IDEC-152 (IDEC / Seikagaku), a primatized anti-CD23 antibody; Humanized anti-CD3 IgG SMART anti-CD3 (Protein Design Lab); Humanized anti-complement factor 5 (C5) antibody 5G1.1 (Alexion Pharm); Human anti-TNF-α antibody adalimumab (HUMIRA, CAT) CDP870 (Celltech) which is a Fab fragment of humanized anti-TNF-α; MDX-CD4 which is a human anti-CD4 IgG antibody (Medarex / Eisai / Genmab); CDP571 which is a humanized anti-TNF-α IgG4 antibody (Abbott); Cel tech); humanized anti-α4β7 antibody, LDP-02 (LeukoSite / Genentech); humanized anti-CD4 IgG antibody, OrthoClone OKT4A (Ortho Biotech); humanized anti-CD40L IgG antibody, ANTOVA (Biogen); VLA-4 IgG antibody ANTEGREN (Elan); human CD64 (FcγR) antibody 30 MDX-33 (Medarex / Centeon); humanized anti-IL-5 IgG4 antibody SCH55700 (Celltech / Schering); humanized respectively Anti-IL-5 and IL-4 antibodies SB-240563 and SB-240683 (SmithKline Beecham); humanized anti-IgE IgG1 antibody rhuMab E25 (Genentech / Norvartis / Tanox Biosystems); murine anti-CD-147 IgM antibody, ABX-CBL (Abgenix); rat anti-CD2 IgG antibody, BTI-322 (Medimune / Bio Transplants); murine anti-CD3 Orthoclone / OKT3 (Ortho Biotech); SIMULECT (Novartis Pharm) which is a chimeric anti-CD25 IgG1 antibody; LDP-01 (LeukoSite) which is a humanized anti-β2-integrin IgG antibody; Anti- which is a murine anti-CD18F (ab ′) ₂ LFA-1 (Pasteur-Merieux / Immunotech); CAT-152 (human anti-TGF-β2 antibody) Cambridge Ab Tech); and CORSEVIN M (Centocor), a chimeric anti-factor VII antibody. The immunoactive agents listed above, as well as any other immunoactive agent, should be administered according to any therapeutic method known to those skilled in the art, including those recommended by the supplier of the immunoactive agent. Can do.

  In other embodiments, the agent used in combination with CP-675,206 is a hepatocyte growth factor receptor (HGFR or c-MET) antagonist.

  In other embodiments of the invention, CP-675,206 or ipilimumab is administered with an antibody against MAdCAM to treat cancer.

  Nucleotide sequences encoding antibodies or other immunoactive agents can be obtained from any information available to those skilled in the art (ie, from Genbank, literature, or by conventional clones). If a clone containing a nucleic acid encoding a particular antibody or epitope-binding fragment or other immunoactive agent is not available, but the sequence of the antibody molecule or epitope-binding fragment or other immunoactive agent is known, an immunoglobulin or Nucleic acids encoding other immunoactive agents can be chemically synthesized, or by any method including, for example, PCR amplification using synthetic primers that can hybridize to the 3 ′ and 5 ′ ends of the sequence, or By cloning using an oligonucleotide probe specific for a particular gene sequence and identifying, for example, a cDNA clone from a cDNA library encoding the antibody, the appropriate source (eg, antibody cDNA library, or antibody Selected hybridoma cells that express Any tissue or cDNA library or nucleic acids isolated therefrom were prepared from cells expressing the body, preferably can be obtained from the poly A + RNA).

  Anti-CTLA4 antibodies, as well as any other second antibody administered therewith, are also eg interleukins (eg IL-1α, IL-1β, 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 (eg, IFNα, IFNβ, IFNγ), tumor necrosis Factors (eg, TNFα, TNFβ), G-CSF, GM-CSF, TGF-β, SLC, endothelial monocyte activation protein-2 (EMAP2), cytokines such as MIP-3α, MIP-3β or HLA-B7 Can be administered together with the MHC gene.

  In one embodiment, CTLA4 blockade occurs simultaneously with IL-15 or agonist administration thereof to increase, induce or prolong the immune response. This is because CTLA4 blockade induces rejection of transplanted islet cells, whereas inhibition of the IL-15 / IL-15R process inhibits CD8 + T cell activation, thereby increasing immune tolerance and grafting. This is because research has shown that rejection is prevented. That is, the graft was rejected by blocking with anti-CTLA4, but blocking IL-15 had the opposite effect. See Ferrari-Lacraz et al., Transplantation 82: 1510-1517 (2006). Thus, when a reduction in immune tolerance is desired, eg, when induction of an anti-tumor immune response in a patient is desired, co-administration of a CTLA4 antagonist in combination with an agonist of IL-15 or IL-15 / IL-15R Can enhance a therapeutic anti-tumor response, can result in a greater immune response than either agent alone, and more preferably, provides a synergistic effect that is greater than the additive effect of each agent combined. it can. Accordingly, in one embodiment of the present invention, anti-CTLA4 antibodies and agonists of the IL-15 / IL-15R signaling pathway that induce, increase and / or prolong the immune response (eg, inter alia IL-15, agonist anti-IL -15 antibodies, agonist anti-IL-15R antibodies) are provided.

  Further exemplary cytokines include, but are not limited to, TNF-α related apoptosis inducing ligand (TRAIL), TNF-α related activation inducing cytokine (TRANCE), TNF-α related weak apoptosis inducer (TWEAK), CD40 ligand (CD40L), LT-α, LT-β, OX40L, FasL, CD27L, CD30L, 4-1BBL, APRIL, LIGHT, TL1, TNFSF16, TNFSF17, and other components of the TNF family including AITR-L, or There is a functional part. For a general review of the TNF family, see, eg, Kwon et al., Curr. Opin. Immunol. 11: 340-345 (1999).

  In one embodiment, interferon and many other immune enhancing agents that can be used in combination therapy with CP-675,206 include, but are not limited to, interferon alpha, interferon alpha-2a, interferon alpha-2b. , Interferon β, interferon γ-1a, interferon γ-1b (Actimmune), or interferon γ-n1, PEG intron A, and combinations thereof. Other agents include interleukin 2 agonists (Aldesleukin, BAY-50-4798, Ceplene (histamine dihydrochloride), EMD-273063, MVA-HPV-IL2, HVA-Muc-1-IL2, interleukin 2, Teseleukin and Virulizin, etc.), Ampligen, Canvaxin, CeaVac (CEA), Denileukin, Filgrastim, Gastrimmune (G17DT), Gemtuzumab Ozogamicin, Glutoxim (BAM-002), GMK vaccine (Progenic 90) (Stressgen HspE7, AG-858, KOS-953, MVJ-1-1, STA-4783, etc.), imiquimod, krestin (polysaccharide K), wrench , Melacine (Corixa), MelVax (mitumomab), Molegramostim, Oncophage (HSPPC-96), OncoVAX (including OncoVAX-CL and OncoVAX-Pr), Olegobomab, Salgramin Pemtumomab (Y-muHMFG1), Pisibanil, Provenge (Dendreon), Ubenimex, WF-10 (Immunokine), Z-100 (Zeria's Anchor-20), Lenalidomide (REVIMID, e) There is that combination.

  The present invention relates to the simultaneous use of an anti-CTLA4 antibody, or a combination of such antibodies, and at least one T cell costimulatory molecule (also referred to herein as “costim”), including but not limited to CD4, CD25, etc. Including administration. Furthermore, costimulatory molecules include, for example, PD-1, B7-H3, OX40, ICOS, CD30, HLA-DR, MHCII, and LFA, or agonist antibodies thereto. These and other costs are well known in the art and are described in 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).

  In an alternative embodiment of the invention, CP-675,206 or ipilimumab is administered with an antibody against human 4-1BB to treat cancer. Suitable anti-4-1BB antibodies are described, for example, in international application PCT / US2004 / 033587 (published on April 21, 2005 as WO 2005/035584). One such antibody is BMS66513.

  In other embodiments of the invention, CP-675,206 or ipilimumab is administered with an antibody against human mucosal addressin cell adhesion molecule (MAdCAM) to treat cancer. Suitable anti-MAdCAM antibodies are described, for example, in the international application PCT / US2005 / 000370 (published on July 28, 2005 as WO 2005/067620). Preferably, the anti-MAdCAM antibody is 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, comprising the heavy and light chain variable region amino acid sequences.

  It will be appreciated that in combination with anti-CTLA4 and immunostimulatory compounds, in addition to increasing the anti-tumor immune response, certain immunosuppressive molecules can inhibit or reduce the anti-tumor response. Thus, in another embodiment of the invention, the anti-CTLA antibody is administered in combination with an inhibitor of an immunosuppressive molecule. Such immunosuppressive molecules include, but are not limited to, IDO, TGF-β, PD-1, among others. Thus, the combination of blocking by anti-CTLA4 and inhibition of other immune regulatory pathways is encompassed by the present invention, thereby further enhancing the anti-tumor response provided by blocking by anti-CTLA4.

  The therapeutic methods described herein include anti-angiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-II (cyclooxygenase II) inhibitors. They can be used together and can be used in conjunction with antibodies in the methods of the invention. Examples of useful COX-II inhibitors include CELEBREX (celecoxib), parecoxib, delacoxib, ABT-963, COX-189 (lumiracoxib), BMS347070, RS57067, NS-398, Bextra (valdecoxib), Vioxx (rofecoxib) SD-8381, 4-methyl-2- (3,4-dimethylphenyl) -1- (4-sulfamoyl-phenyl) -1H-pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4 -Sulfamoylphenyl) -1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (ethricoxib). In addition, COX-II inhibitors are disclosed in US patent application Ser. Nos. 10 / 801,446 and 10 / 801,429, the entire contents of which are incorporated for all purposes.

  In one embodiment, the agent is celecoxib disclosed in US Pat. No. 5,466,823, the entire contents of which are incorporated by reference for all purposes. In other embodiments, the agent is deracoxib disclosed in US Pat. No. 5,521,207, the entire contents of which are incorporated by reference for all purposes.

  Other useful anti-angiogenic inhibitors for use in conjunction with CP-675,206 non-selectively inhibit prostaglandin-producing enzymes (cyclooxygenase I and II), resulting in prostaglandin levels. There are aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) that lower blood pressure. Such agents include, but are not limited to, Aposyn (exislind), salsalate (Amigesic), diflunisal (Dolobid), ibuprofen (Motrin), ketoprofen (Orudis), nabumetone (Relafen), piroxicam (Feldene), Naproxen (Alev, Naprosyn), Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketrolac (Toradol), and Oxaprozin (Daypro), and combinations thereof.

  Preferred non-selective cyclooxygenase inhibitors include ibuprofen (Motrin), new purine, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen), and combinations thereof.

  Other anti-angiogenic compounds include acitretin, angiostatin, apyridine, cilentide, COL-3, combretastatin A-4, endostatin, fenretinide, halofuginone, Panzem (2-methoxyestradiol) , PF03446962 (ALK-1 inhibitor), levimastat, levomab (removab), Revlimid, squalamine, thalidomide, ukulein, Vitaxin (α-v / β-3 integrin), and zoledronic acid.

  Useful matrix metalloproteinase inhibitors are described in International Patent Publications WO96 / 33172; WO96 / 27583; WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, European Patent Application No. 780386 (published on June 25, 1997), 97304971 (filed on July 8, 1997), 99308617 (October 29, 1999) No. 606046 (published on July 13, 1994), 931788 (published on July 28, 1999), 99302232 (filed on March 25, 1999), international application PCT / IB98 / 01 13 (filed on July 21, 1998), British Patent Application No. 99129961 (filed on June 3, 1999), US Provisional Patent Application No. 60 / 148,464 (filed on August 12, 1999) And in US Pat. Nos. 5,863,949 and 5,861,510.

  Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred inhibitors are other matrix metalloproteinases (ie MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, It selectively inhibits MMP-2 and / or MMP-9 compared to MMP-12 and MMP-13).

Some specific examples of MMP inhibitors useful in the present invention include AG-3340, RO 32-3555, RS 13-0830, ABT-510 (Abbott), ABT 518 (Abbott), Apatata (Amgen), AZD 8955 (AstraZeneca), Neovostat (AE-941), COL 3 (CollaGenex Pharmaceuticals), doxycycline hycrate, MPC 2130 (Myriad), PCK 3145 (Procion), and compounds listed below:
3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid;
3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
(2R, 3R) 1- [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid;
4- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
(R) 3- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide;
(2R, 3R) 1- [4- (4-Fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid;
3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid;
3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and (R) 3- [ 4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid hydroxyamide;
And pharmaceutically acceptable salts and solvates of the aforementioned compounds.

  In other embodiments, the agent is a signaling inhibitor. Such inhibitors include small molecules, antibodies, and antisense molecules, including tyrosine kinase inhibitors, serine / threonine kinase inhibitors. More specifically, signal transduction inhibitors include farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, generalized erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors and WNT pathway inhibitors, and There are so-called multi-targeted kinase inhibitors.

  In other embodiments, the signaling inhibitor is a farnesyl protein transferase inhibitor. Farnesyl protein transferase inhibitors include US Pat. No. 6,194,438, issued February 27, 2002; US Pat. No. 6,258,824, issued July 10, 2001; US Pat. , 586,447, issued July 1, 2003; US Pat. No. 6,071,935, issued June 6, 2000; and US Pat. No. 6,150,377, November 21, 2000. There are compounds disclosed in the day issued and claimed. Other farnesyl protein transferase inhibitors include AZD-3409 (AstraZeneca), BMS-214662 (Bristol-Myers Squibb), Lonafarnib (Sarasar) and RPR-115135 (Sanofi-Aventis). Each of the above patent applications and provisional patent applications are hereby incorporated by reference in their entirety.

  In other embodiments, the signaling inhibitor is a GARF inhibitor. Preferred GARF inhibitors (glycinamide ribonucleotide formyltransferase inhibitors) include Pfizer AG-2037 (peritrexol) and pharmaceutically acceptable salts thereof. GARF inhibitors useful in the practice of the present invention are disclosed in US Pat. No. 5,608,082, which is incorporated in its entirety for all purposes.

  In other embodiments, the signaling inhibitor is a MEK inhibitor. MEK inhibitors include Pfizer's MEK1 / 2 inhibitor PD325901, Array Biopharm's MEK inhibitor ARRY-142886, and combinations thereof.

  In other embodiments, the anti-cancer signaling 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.

  In other embodiments, the anti-cancer signaling inhibitor is an Aurora2 inhibitor such as VX-680 and its derivatives (Vertex), R 763 and its derivatives (Rigel), ZM 447439 and AZD 1152 (AstraZeneca), or Checkpoint kinase 1/2 inhibitor, such as XL844 (Exilixis).

  In other embodiments, the anti-cancer signaling inhibitor is an Akt (protein kinase B) inhibitor, such as API-2, perifosine or RX-0201.

  In addition, other targeted anticancer agents include sorafenib (BAY-43-9006, Bayer / Onyx), GV-1002, ISIS-2503, LE-AON and GI-4000, BMS 184476, CCI 779, DTIC, ISIS There are 2503, ONYX 015, and flavopiridol.

  The present invention also includes CP-675,206 and CDK2 inhibitors ABT-751 (Abbott), AZD-5438 (AstraZeneca), arbocidib (flavopiridol, Aventis), BMS-387,032 (SNS 032, Bristol Myers). , EM-1421 (Erimos), indislam (Esai), sericin crib (Cyclcel), BIO 112 (Onc Bio), UCN-01 (Kyowa Hakoko), and AT7519 (Astex Therapeutics) and Pfizer 1 PD03 It also relates to a method comprising a cell cycle inhibitor such as AG24322.

  The present invention also includes CP-675,206 with telomerase inhibitors such as transgenic B lymphocyte immunotherapy (Cosmo Bioscience), GRN 163L (Geron), GV1001 (Pharmexa), RO 254020 (and derivatives thereof) and diazaphyronic acid. Also related to the use of.

  The present invention also includes, but is not limited to, toremifene, antiestrogens including raloxifene, antiandrogens such as finasteride, mifepristone, ABARELIX (Praecis), TRELSTAR, ATAMESTANE (Biomed-777), ATRASETEN (Xinlay), Bosentan, It also relates to the use of CP-675,206 in conjunction with hormones such as doxel calciferol, and combinations thereof, antihormones, antiandrogens therapeutic agents.

  The present invention also includes histones such as suberoylanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101. Also contemplated is the use of CP-675,206 in conjunction with gene silencing agents or gene activating agents such as acetylase (HDAC) inhibitors.

  The invention also uses CP-675,206 with gene therapy agents such as ADVEXIN (ING 201), TNFerrade (GeneVec, a compound that expresses TNFα in response to radiation therapy), RB94 (Baylor Medical University), etc. Is also intended.

  The present invention also contemplates the use of CP-675,206 in conjunction with a ribonuclease such as Onconase.

  The present invention also contemplates CP-675,206 with antisense oligonucleotides such as the bcl-2 antisense inhibitor Genasense (Oblimersen, Genta).

  The present invention also contemplates CP-675,206 with proteasome agonists such as PS-341 (MLN-341) and VELCADE (bortezomib).

  The present invention also contemplates CP-675,206 with an anti-vascular agent such as combretastatin A4P (Oxigen).

  The present invention also includes CP-675,206 and conventional cytotoxic agents including DNA binding agents, mitotic inhibitors, alkylating agents, antimetabolites, insertion antibiotics, topoisomerase inhibitors and microtubule inhibitors. It is also intended to be used in combination.

  In an embodiment of the invention, the anti-CTLA4 antibody is administered to a patient receiving a chemotherapeutic agent for treating cancer. Such chemotherapeutic agents are known in the art and include, but are not limited to, methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosourea, Cisplatin, carboplatin, mitomycin, dacarbazine, procarbazine, etoposide, camptothecin, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, prikamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxin, docetaxin Taxanes such as 5-fluorouracil, docetaxel and paclitaxel, leucovorin, levamisole, Nitrosoureas such as linotecan, estramustine, etoposide, carmustine and lomustine, L-asparaginase, topotecan, nitrogen mustard, cytoxan, etoposide, BCNU, vinca alkaloid, platinum compound, mitomycin, gemcitabine, hexamethylmelamine, temsirolimus (CCI -779); lapatinib (GW 572016); RAD-001 (everolimus); XRP-9881; ixabepilone (BMS-247550); pertuzumab (OMNITARG, 2C4); topotecan, tyrosine kinase inhibitor, tyrphostin, imatinib mesylate (GLEEVEC) , Herbimycin A, genistein, ervstatin, and lavendustin A.

In other embodiments, suitable chemotherapeutic agents include, but are not limited to, alkylating agents: nitrogen mustard (e.g., cyclophosphamide, among other agents known in the art). Ifosfamide, trophosphamide, chlorambucil); nitrosourea (eg, carmustine (BCNU), lomustine (CCNU)); alkyl sulfonate (eg, busulfan, treosulphan); triazene (eg, dacarbazine); platinum-containing compound (eg, cisplatin) Plant alkaloids: vinca alkaloids (eg, vincristine, vinblastine, vindesine, vinorelbine); taxoids (eg, paclitaxel, docetaxel); DNA topois Merase inhibitors: epipodophyllin (eg, etoposide, teniposide, topotecan, 9-aminocamptothecin, camptothecin, crisnatol); mitomycin (eg, mitomycin C, antimetabolite); folate antimetabolite; DHFR inhibitor Agents (eg, methotrexate, trimethrexate); IMP dehydrogenase inhibitors (eg, mycophenolic acid, thiazofurin, ribavirin, EICAR); ribonucleotide reductase inhibitors (eg, hydroxyurea, deferoxamine); pyrimidine analogues: uracil analogues (Eg 5-fluorouracil, floxuridine, doxyfluridine, raltitrexed); cytosine analogues (eg cytarabine (ara C), cytosine ara Noside, fludarabine); purine analogs (eg, mercaptopurine, thioguanine); DNA antimetabolites (eg, 3-HP, 2′-deoxy-5-fluorouridine, 5-HP, α-TGDR, aphidicolin glycinate, ara-C, 5-aza-2′-deoxycytidine, β-TGDR, cyclocytidine, guanazole, inosine glycodialdehyde, macebesin II, pyrazoloimidazole); hormone therapy: receptor antagonist: antiestrogens (eg, tamoxifen , Raloxifene, megestrol); aromatase inhibitors (eg, exemestane, anastrozole, letrozole); GnRH antagonists (eg, abarelix, histrelin); selective estrogen receptor modulators (SERM) (eg, Lasofoxifene); LH-RH agonists (eg goserelin, triptorelin, buserelin, leuprolide acetate); antiandrogens (eg flutamide, bicalutamide, nilutamide, megestrol, cyproterone); retinoid / deltoid: cis retinoic acid; vitamin A derivatives (eg, all-trans retinoic acid (ATRA-IV)); vitamin D3 analogs (eg, EB 1089, CB 1093, KH 1060); photodynamic therapy (eg, belt porphin (BPD-MA), phthalocyanine, Photosensitizer Pc4, demethoxy-hypocrellin A (2BA-2-DMHA)); cytokines such as IL-1α, IL-1β, IL-2, IL-3, IL-4, IL − IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, IL-18, IFNα, IFNβ, IFNγ, TNFα, TNFβ, G-CSF , GM-CSF, TGF-β, SLC, EMAP2, MIP-3α, MIP-3β, HLA-B7, other components of the TNF family (eg, TRAIL, TRANCE, TWEAK, CD40L, LT-α, LT-β , OX40L, CD40L, FasL, CD27L, CD30L, 4-1BBL, APRIL, LIGHT, TL1, TNFSF16, TNFSF17, and AITR-L, or a functional part thereof); angiogenesis inhibitor: angiostatin (plasminogen fragment) Antiangiogenic antithrombin III, angiozyme , ABT-627, Bay 12-9566, benefin, bevacizumab, BMS-275291, cartilage-derived inhibitor (CDI), CAI, CD59 complement fragment, CEP-7055, Col 3, combretastatin A-4, endostatin ( Collagen XVIII fragment), fibronectin fragment, Gro-β, halofuginone, heparinase, heparin hexasaccharide fragment, HMV833, human chorionic gonadotropin (hCG), IM-862, interferon α / β / γ, interferon inducible protein (IP-10) ), Interleukin-12, Kringle 5 (plasminogen fragment), marimastat, metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, MMI 270 (CGS 27023A), MoAb IMC-1C11, Neobasstat (Aeterna), NM-3, Panzem, PI-88, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor 4 (PF4), purinomastert, prolactin 16 kD fragment, Proliferin-related protein (PRP), PTK 787 / ZK 222594, retinoid, sorimastat, squalamine, SS 3304, SU 5416, SU6668, SU11248, SU12662, SU14813, BAY 43-9906, AG-01 -S, tetrathiomolybdate, thalidomide, thrombospondin-1 (TSP-1), TNP-470, transforming growth factor -Β (TGF-b), vasculostatin (vasculostatin), vasostatin (calreticulin fragment), ZD6126, ZD 6474, farnesyltransferase inhibitor (FTI), bisphosphonate; antimitotic agents (eg, arocolchicine ( allocolchicine), halichondrin B, colchicine, colchicine derivatives, dolstatin 10, maytansine, lysoxine, thiocolchicine, tritylcysteine); other agents: isoprenylation inhibitors; dopaminergic neurotoxins ( For example, 1-methyl-4-phenylpyridinium ion); cell cycle inhibitors (eg, staurosporine); actinomycin (eg, actinomycin D) Bleomycin (eg, bleomycin A2, bleomycin B2, pepromycin); anthracycline (eg, daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, sorbicin, mitoxantrone); mTOR inhibitor (eg, Temsirolimus, everolimus); MDR inhibitors (eg verapamil); Ca ²⁺ ATPase inhibitors (eg capsigardin); toll-like receptor agonists (eg CPF-7909, also called PF03512676 or PROMUNE; Corey Pharm; Krieg, 1998) "Applied Oligonucleotide Technology", pages 431-448, C.I. A. Stein and A.M. M.M. Krieg (eds.), John Wiley and Sons, Inc. Co-stimulatory molecules (eg, CD4, CD25, PD-1, B7-H3, 4-1BB, OX40, ICOS, CD30, HLA-DR, MHCII, and LFA, and the like) Agonistic antibodies).

  Additional anti-cancer agents that can be used in the methods of the present invention include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; achronin; adzelesin; altrethamine; altomycin, ambomycin, amethothrone acetate; Aminglutetimide; Amsacrine; Anastrozole; Anthromycin; Arsenic trioxide; Asparaginase; Asperlin; Asperitin; Bisantren; bisnafidodimesylate; biselecin; bleomycin sulfate; bortezomib; brequinar natri Carpisine hydrochloride; carbolamicil; chlorambucil; cylolecillincine; carlesine hydrochloride; Crisnatol; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; darbepoetin; daunorubicin hydrochloride; decitabine; dexsolmaplatin; Dororoxifene Droloxifen citrate; drmostanolone propionate; duazomycin; farmorubicin; edatrexate; efflornitine hydrochloride; elsamitrucin; enroplatin; enpromate; epipropidin; Esorubicin (esorubicin) hydrochloride; estramustine phosphate; sodium ethanidazole; etoposide; etoposide phosphate; etoprine; everolimus; exemestane; CSF); floxuridine; fludarabine phosphate; fludrocortisone; fluorouracil; fluoxymesterone; flulocitabine; hoskidone; hostelicin sodium; fulvestrant; gefitinib; gemcitabine; gemcitabine hydrochloride; gemtuzumab; Ritumomab tiuxetane; idarubicin hydrochloride; ifosfamide; ilmofosin; imatinib; interleukin II (including recombinant interleukin II or rIL2); interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; Interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; ixabepilone; ketoconazole; lanreotide acetate; Lapatinib; letrozole; leucovorin; leuprolide acetate; levamisole; riarosol hydrochloride; lometrexol sodium; lomustine; rosoxantrone hydrochloride; masoprocol; Mercaptopurine; Messna; Methotrexate; Methotrexate sodium; Metopurine; Mestrepa; Mitintimide; Mitocarcin; Mitocromin; Mitodiline; Nocodazole; nogaramicin; Oleplatin; Oxaliplatin; Oxaliplatin; Paclitaxel; Pamidronate; Pegaspargase; PEG-L-aspargase; PEG-filgrastim; Piprobroman; Piposulfan; Piroxantrone hydrochloride; Prikamycin; Promestan; Porfimer sodium; Porphymer; Porphyromycin; Prednimustine; Pemetrexed; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Rituxima Slogin; sapultol; symtrazen; samtrazen; sombadene; PEGVISOMANT; sparfosate sodium; spalomycin; spirogermanium hydrochloride; spiromustine; Tezomycin; Talisomycin; Tecogalane sodium; Tegafur; Teloxantrone hydrochloride; Temoporphine; Temozolomide; Tretinoin; trestron acetate eciate); Triciribine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Topotecan hydrochloride; Tubrosol hydrochloride; Uracil mustard; Uredepa; Vapelotide; sulfate; binglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; zorodrosate; orubicin hydrochloride) there is.

  Other anti-cancer drugs that can be used include, but are not limited to, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; ALL-TK antagonist; altretamine; amambastin; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; Morphogenic protein-1; antiandrogen, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; Apoptotic gene regulator; apoptotic regulator; aprinic acid; ara-CDP-DL-PTBA; arginine deaminase; asuracline; atamestan; atritin; axinastatin 1; axinastatin 2; Statins 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorin; benzoylstaurosporine; β-lactin derivatives; ); Betaclamicin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyl Permin; bisnafide; bistratene A; biselecine; breflate; broprimine; budotitanium; buthionine sulphoximine; calcipotriol; calphostin C; camptothecin derivative; canarypox IL-2; capecitabine; Triazole; Carboxamide triazole; CaRest M3; CARN700; Cartilage-derived inhibitor; Calzeresin; Casein kinase inhibitor (ICOS); Castanospermine; Cecropin B; Setrorelix; Chlorin; Chloroquinosaline sulfonamide; Cicaprost; Clomiphene analog; clotrimazole; collismycin A; chorismycin B Combretastatin A4; combretastatin analog; conagenin; clambecidin 816; crisnatol; cryptophysin 8; cryptophysin A derivative; curacin A; cyclopentanthraquinone; cycloplatomycin; Cytarabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexfosfamix; dexfosfamix; Diazocon; Daidemnin B; Da Dioxordin; Dihydroxy-5-azacytidine; 9-Dihydrotaxol; Dioxamycin; Diphenylspiromusine; Docetaxel; Docosanol; Dorasetron; Doxyfluridine; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosin; Edrecolomab; Eflornithine; Elemene; Emiteful; Epirubicin; Epristeride; Flavopyridol; Frezelastine; Fluasterone Fludarabine; fluorodaunoornicin hydrochloride; phorphenimex; formestane; hostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; Hexamethylenebisacetamide; hyperidine; ibandronic acid; idarubidine; idoxifene; idramanton; ilmofosin; ilomasterat; imidazoacridone; imiquimod; immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitor; interferon agonist; interferon; Iobenguan; iododoxol 4-Ipomeanol; iropract; irsogladine; isobengazole; isohomohalindrin B; ilacetron; jaspraquinolide; kahalalide F; kahalalide F; Reinamycin; Lenograstim; Lentinan sulfate; leptolstatin; letrostatin; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprolidene; levamisole; liarozole; linear polyamine analog; A lipophilic platinum compound; lithoclinamide 7 e 7); Lovaplatin; lombricin; lometrexol; lonidamine; rosoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; Matrix metalloproteinase inhibitors; menogalyl; merbarone; methaleline; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitguazone; mitactol; mitomycin analogue; Toxin fibroblast growth factor-saponin; Mitoxantrone Morpholamostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A + myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor gene 1 based therapy; mustard anticancer agent; (Mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyldinarine; N-substituted benzamide; nafarelin; nagrestip (nagrestip); naloxone + pentazosin; napabin; Narutograstim; nedaplatin; nemorubicin; neridronate; neutral endopep Nitamide; nisamicin; nitric oxide modulator; nitroxide antioxidant; nitrullin; O6-benzylguanine; octreotide; oxenone; oligonucleotide; onapristone; ondansetron; Oracin; oral cytokine inducer; ormaplatin; osalarone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analog; paclitaxel derivative; parauamine (palaamine); palmitoyl lysoxin; Panomiphene; parabactin; pazelliptin; pegaspargase; Pentosan sodium polysulfate; pentostatin; pentrozole; perflubrone; perphosphamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitor; pisibanil; pilocarpine hydrochloride; pirarubicin; pyretrexim; Plastin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porphyromycin; prednisone; propylbisacridone; prostaglandin J2; proteasome inhibitor; A based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitor; microalgal; protein Tyrosine phosphatase inhibitor; purine nucleotide phosphorylase inhibitor; purpurine; pyrazoloacridine; pyridoxyl oxidized hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; Demethylated retelliptin; etidronate rhenium Re186; lysoxine; ribozyme; RII retinamide; logretimide; rohitukine; romutide; rokinimex; rubiginone B1; ruboxinsign; Sarcophytol A; Sargramostim; Sdi1 Substance: Semustine; Aging-derived inhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Single chain antigen binding protein; Schizofuran; Sobuzoxane; Sodium borocaptate; Sodium phenylborocapate; Somatomedin-binding protein; sonermine; sparfolic acid; spicamycin D; spiromustine; splenopentin; sponge statin 1; squalamine; stem cell inhibitor; stem cell mitotic inhibitor; stipamide; stromelysin inhibitor; sulfinosine; Active intestinal peptide antagonist; slistas; suramin; swansonine; synthetic glycosaminoglycan; talimustine; tamoxifen Tauromustine; Tazarotene; Tecogalane sodium; Tagafur; Tellurapyrylium; Telomerase inhibitor; Temoporfin; Temozolomide; Teniposide; Thymalfacin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurine; tirapazamine; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitor; tretinoin; triacetyluridine; Trimetrexate; Triptorelin; Troposterol; Tyrosteride; Tyrosine kinase inhibitor; Tyrophostin; UBC inhibitor; Ubenimex; Urogenital sinus-derived growth inhibitor; Urokinase receptor antagonist; Vapreotide; Variolin B; Vector system, erythrocyte gene therapy; Bellaresol; Veramine; (Vertin); verteporfin; vinorelbine; vinxartine; vitaxin; borosol; zanoterone; xeniplatin; dilascorb;

  In other specific embodiments, a combination comprising an anti-CTLA4 antibody and a second therapeutic agent is administered to a subject undergoing radiation therapy to treat cancer. In radiotherapy, the radiation may be γ rays or X rays. This method includes external beam radiotherapy, intrastromal implantation of radioisotopes (I-125, palladium, iridium), radioisotopes such as strontium-89, chest radiotherapy, intraperitoneal P-32 radiotherapy, and / or Or cancer treatment including radiation therapy such as whole abdominal and pelvic radiation therapy. In preferred embodiments, radiation treatment is performed as external beam radiation or teletherapy, and radiation is delivered from a remote source. In various preferred embodiments, radiotherapy is performed as internal therapy or brachytherapy, and the radioactive source is placed in the body close to the cancer cells or tumor mass. Radiation therapy can be performed according to well-known methods of radiation therapy for treating cancer. The dose and method of radiation therapy can be readily determined by those skilled in the art and is based on the stage of the disease and other factors well known in the art. For a general overview of radiation therapy, see Hellman, “Principles of Cancer Management: Radiation Therapy”, Chapter 16, DeVita et al., 6th edition, 2001, J. Am. B. See Lippencott Company, Philadelphia.

  Simultaneous administration of antibody and at least one therapeutic agent (combination therapy) includes administration of a pharmaceutical composition comprising both an anti-CTLA4 antibody and one or more therapeutic agents, and one includes an anti-CTLA4 antibody , Others include the administration of two or more separate pharmaceutical compositions comprising the therapeutic agent (s). Furthermore, co-administration or combination (joint) therapy generally means that the antibody and the additional therapeutic agent are administered simultaneously with each other, but it also administers the individual components of the treatment simultaneously, sequentially or separately. Is also included. It is further understood that when the antibody is administered intravenously and the therapeutic agent is administered orally (eg, exemestane), preferably the combination is administered as two separate pharmaceutical compositions.

  The invention also provides for administering other therapeutic agents in addition to the antibody and the first therapeutic agent, simultaneously with one or more of these components, or sequentially before and / or after. Is also included. Such therapeutic agents include cancer vaccines, anti-vascular agents, anti-proliferative agents, anti-angiogenic agents, signal transduction inhibitors, immunomodulators, cytokines, and but are not limited to analgesics, antiemetics, There are palliatives that provide symptomatic treatments such as antidiarrheals and steroids. Preferred antiemetics include ondansetron hydrochloride, granisetron hydrochloride, and metoclopramide. Preferred antidiarrheals include diphenoxylate and atropine (LOMOTIL), loperamide (IMMODIUM), octreotide (SANDOSTATIN), olsalazine (DIPENTUM), and mesalamine (ASACOL). Preferred steroids include the non-absorbable steroids budesonide (ENTOCORT), systemic steroids dexamethasone (DECADRON) and prednisone (METICORTEN).

  Each administration can vary from rapid administration to continuous perfusion over its duration. As a result, for the purposes of the present invention, the combinations are not exclusively limited to those obtained by physical association of the components, some may be administered separately, and the administration may be simultaneous, Or you may leave a fixed period interval. The composition according to the invention is preferably a composition that can be administered parenterally. However, this composition may be administered orally or in the peritoneal route in the case of localized topical therapy.

  As will be appreciated by those skilled in the art, the choice of therapeutic agent to be used in combination with an anti-CTLA4 antibody and the timing of its use will be determined in part by the type and stage of the cancer being treated.

  The methods of the present invention are suitable for use as both first-line therapy and second-line therapy. Treatment of both early stage cancer and advanced (metastatic) cancer is within the scope of the present invention.

V. Pharmaceutical composition The present invention comprises a therapeutic agent such as a chemotherapeutic agent, another antibody, an immunostimulatory agent, a signal transduction inhibitor, an angiogenesis inhibitor, and the human anti-CTLA4 antibody of the present invention as an active ingredient Preferably, the therapeutic agent is a chemotherapeutic agent. Such pharmaceutical compositions consist of only each active ingredient (eg, an effective amount of anti-CTLA4, an effective amount of a therapeutic agent) as a combination of at least one active ingredient in a form suitable for administration to a subject. Alternatively, the pharmaceutical composition may comprise an active ingredient and one or more pharmaceutically acceptable carriers, one or more additional (active and / or inactive) ingredients, or some combination thereof. May be included.

  In one embodiment, the antibody is administered parenterally (eg, intravenously) in an aqueous solution, while the therapeutic agent (eg, chemotherapeutic agent, signal transduction inhibitor, immunomodulator, angiogenesis inhibitor, etc.) is administered in a round. Orally administered in the form of a drug / capsule. However, one of ordinary skill in the art will understand based on the disclosure provided herein that the invention is not limited to this or any other formulation, dosage, route of administration, and the like. Rather, the present invention includes, but is not limited to, administering each agent separately in different formulations via different routes of administration, and a single composition as an aqueous composition that is administered intravenously, among many others. Administering the antibody in combination with a therapeutic agent, including administering the antibody and therapeutic agent in a product (eg, where the therapeutic agent is a protein such as another antibody, cytokine, costim) Any formulation or method of Accordingly, the following discussion describes various formulations for practicing the methods of the invention involving the administration of any anti-CTLA4 antibody in combination with any therapeutic agent, but the invention includes those formulations. It includes, but is not limited to, any formulation that can be readily determined by one of ordinary skill in the art after having learned the teachings provided herein for use in the methods of the invention.

  In certain embodiments, the antibody may exist in a neutral form (including zwitterionic form) or may exist as a positively or negatively charged species. In some embodiments, the antibody can be complexed with a counterion to form a pharmaceutically acceptable salt.

  The term “pharmaceutically acceptable salt” refers to a complex comprising one or more antibodies and one or more counterions, where the counterions are bound to pharmaceutically acceptable inorganic and organic acids and bases. Derived from.

  Pharmaceutically acceptable inorganic bases include metal ions. More preferred metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, cobalt, nickel, molybdenum, vanadium, manganese, chromium, selenium, tin, copper, ferric, ferrous, lithium, at their normal valences. There are magnesium, manganous salts, manganous, potassium, rubidium, sodium and zinc.

  Pharmaceutically acceptable acid addition salts of the antibodies of the present invention include, but are not limited to, formic acid, acetic acid, acetamide benzoic acid, adipic acid, ascorbic acid, boric acid, propionic acid, benzoic acid, camphoric acid, carbonic acid, cyclamic acid , Dehydrocholic acid, malonic acid, edetic acid, ethyl sulfuric acid, fendizoic, metaphosphoric acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, tannic acid, citric acid, nitric acid, ascorbic acid, Glucuronic acid, maleic acid, folic acid, fumaric acid, propionic acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, hydrocholic acid, hydrobromic acid, hydroiodic acid, ricinic acid, isocitric acid, trifluoroacetic acid, pamo Acid, propionic acid, anthranilic acid, mesylic acid, orotic acid, oxalic acid, oxaloacetic acid, Inic acid, stearic acid, salicylic acid, aminosalicylic acid, silicic acid, p-hydroxybenzoic acid, nicotinic acid, phenylacetic acid, mandelic acid, embonic acid (embonic), sulfonic acid, methanesulfonic acid, phosphoric acid, phosphonic acid, ethanesulfone Acid, ethanedisulfonic acid, ammonium acid, benzenesulfonic acid, pantothenic acid, naphthalenesulfonic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, sulfuric acid, nitric acid, nitrous acid, sulfuric acid monomethyl ester, cyclohexylaminosulfonic acid, β-hydroxybutyric acid, glycine acid, glycylglycine acid, glutamic acid, cacodylic acid, diaminohexanoic acid, camphorsulfonic acid, gluconic acid, thiocyanic acid, oxoglutaric acid, pyridoxal 5-phosphate, chlorophenoxyacetic acid, unde It can be prepared from acids including canic acid, N-acetyl-L-aspartic acid, galactaric acid and galacturonic acid.

  Pharmaceutically acceptable organic bases include trimethylamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, dibenzylamine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, cyclic amine, Quaternary ammonium cation, arginine, betaine, caffeine, clemizole, 2-ethylaminoethanol, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanediamine, butylamine, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperazine , Ethyl glucamine, glucamine, glucosamine, histidine, hydrabamine, imidazole, isopropylamine, methyl glucamine, morpholine, piperazine, pipe Gin, pyridoxine, neodymium, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, tripropylamine, triethanolamine, tromethamine, methylamine, taurine, cholate, 6-amino-2-methyl-2-heptanol, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and Aromatic sulfonic acid, strontium, tricine, hydrazine, phenylcyclohexylamine, 2- (N-morpholino) ethanesulfonic acid, bis (2-hydroxyethyl) amino-tris (hydroxymethyl) methane, N- (2-acetamido)- 2- Minoethanesulfonic acid, 1,4-piperazine diethanesulfonic acid, 3-morpholino-2-hydroxypropanesulfonic acid, 1,3-bis [tris (hydroxymethyl) methylamino] propane, 4-morpholinepropanesulfonic acid, 4 -(2-hydroxyethyl) piperazine-1-ethanesulfonic acid, 2-[(2-hydroxy-1,1-bis (hydroxymethyl) ethyl) amino] ethanesulfonic acid, N, N-bis (2-hydroxyethyl) ) -2-aminoethanesulfonic acid, 4- (N-morpholino) butanesulfonic acid, 3- (N, N-bis [2-hydroxyethyl] amino) -2-hydroxypropanesulfonic acid, 2-hydroxy-3- [Tris (hydroxymethyl) methylamino] -1-propanesulfonic acid, 4- (2-hydroxyethyl) ) Piperazine-1- (2-hydroxypropanesulfonic acid), piperazine-1,4-bis (2-hydroxypropanesulfonic acid) dihydrate, 4- (2-hydroxyethyl) -1-piperazinepropanesulfonic acid, N, N-bis (2-hydroxyethyl) glycine, N- (2-hydroxyethyl) piperazine-N ′-(4-butanesulfonic acid), N- [tris (hydroxymethyl) methyl] -3-aminopropanesulfone Acid, N-tris (hydroxymethyl) methyl-4-aminobutanesulfonic acid, N- (1,1-dimethyl-2-hydroxyethyl) -3-amino-2-hydroxypropanesulfonic acid, 2- (cyclohexylamino) Ethanesulfonic acid, 3- (cyclohexylamino) -2-hydroxy-1-propanesulfonic acid, 3- (cycl Hexylamino) -1-propanesulfonic acid, N- (2-acetamido) iminodiacetic acid, 4- (cyclohexylamino) -1-butanesulfonic acid, N- [tris (hydroxymethyl) methyl] glycine, 2-amino- There are 2- (hydroxymethyl) -1,3-propanediol and trometamol.

  The anti-CTLA4 antibody used in the methods of the invention can be incorporated into a pharmaceutical composition suitable for administration to a subject. Usually, the pharmaceutical composition comprises the antibody and a pharmaceutically acceptable carrier. As used herein, “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. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable substances, such as minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffering agents, 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 various forms. This includes, for example, liquids (eg, injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liquids such as liposomes and suppositories, semisolid and solid dosage forms There is. The preferred form depends on the therapeutic agent, the intended mode of administration, and therapeutic application. A normally preferred composition is in the form of an injectable or injectable solvent, such as a composition similar to that used for passive human immunization with other antibodies. The preferred mode of administration is parenteral (eg, intravenous, transdermal, intraperitoneal, intramuscular) administration. In preferred embodiments, the antibody is administered by intravenous infusion or injection. In other preferred embodiments, the antibody is administered by intramuscular or transdermal injection.

  A therapeutic composition usually must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solvent, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration. Injectable sterile solvents can be prepared by placing the required amount of antibody in a suitable solvent containing one or a combination of the above-listed ingredients as required, followed by filter sterilization. Generally, dispersions are prepared by placing the active compound in a sterile medium that contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of injectable sterile solvents, the preferred method of preparation is vacuum drying and lyophilization, in which the active ingredient plus any additional desired ingredient powder is obtained from the previously sterile filtered solution. The proper fluidity of a solvent 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 but not limited to oral, parenteral, mucosal, inhalation, topical, buccal, nasal, and rectal administration. For many therapeutic applications, the preferred route / form of administration is transdermal, intramuscular, intravenous or infusion administration. If necessary, needleless injection can be used. As will be appreciated by those skilled in the art, the route and / or form of administration will vary depending on the desired result.

  In certain embodiments, antibodies can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Numerous methods for preparing such formulations are patented or generally known to those skilled in the art. For example, “Sustained and Controlled Release Drug Delivery Systems”, J. Am. R. Edited by Robinson, Marcel Dekker, Inc. , New York (1978).

  Transdermal delivery of biomolecules, including antibodies, cytokines, etc., includes microneedles that create micron-sized temporary transport pathways in the skin and can transport large molecules through that pathway. See, for example, Banga, “Therapeutic peptides and proteins: Formulation, processing and delivery systems”, 2nd edition, Taylor & Francis (ed.), 2006; Martinto et al., J. Biol. Controlled Release 112: 357-361 (2006). In one embodiment, the microneedles include those composed of silicon, metal or polymer. In other embodiments, maltose microneedles that dissolve in the skin are used to administer compositions of the invention, including anti-CTLA4 antibody, anti-CD40, anti-IGF-1R antibody, rituximab, trastuzumab, IL-15, and the like. can do.

  In still other embodiments, a nucleic acid, including a nucleic acid encoding a protein, preferably an anti-CTLA4 antibody (eg, CP-675,206, ipilimumab, etc.), or ODN, is delivered transdermally using a particle gun. Antibody expression or ODN delivery in a microenvironment where antigen presenting cells (eg, dendritic cells) and / or regulatory T cells (eg, Tregs in lymph nodes) are present. Gold microparticles containing a nucleic acid encoding an anti-CTLA4 antibody and / or containing a nucleic acid encoding an ODN or protein of interest can be obtained from, for example, a “gene gun” (PMED Device, eg, Model ND-10, PowderMed Ltd., Fire through the skin using UK Oxford). See, for example, US Pat. Nos. 6,194,389, 6,168,587, and 5,478,744. In one embodiment, a synthetic oligodeoxynucleotide (ODN) toll-like receptor 9 agonist (such as a microparticle comprising a nucleic acid encoding an antibody and a microparticle comprising ODN, or both, is transdermally delivered. For example, PF03512676) can be administered using a particle gun. In other embodiments, TAA is expressed in APCs transfected with nucleic acids and TAA is presented by APC (eg, gp100, tyrosinase, MAGE, MART-1, NY-ESO-1, etc.) Can be delivered transdermally using a particle gun. In still other embodiments, antigens (eg, TAA), antibodies (eg, anti-CTLA4, anti-CD40, anti-CD20, anti-HER2 etc.), cytokines (eg, GM-CSF, IL-15, TNFα, among others), ODN (eg, PF03512676), various combinations of costimulatory molecules (eg, PD-1, OX40, 4-1BB, etc.) are delivered using a particle gun to induce, enhance or prolong an anti-tumor response in a patient. Can do.

  Dosage regimens can be adjusted to provide the optimum desired response. For example, as indicated by the urgency of the treatment situation, a single bolus can be given, several divided doses can be given over time, or the dose can be increased or decreased proportionally You can also. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dosage for the mammalian subject to be treated, each unit with the required pharmaceutical carrier so as to provide the desired therapeutic effect. Containing a predetermined amount of active compound calculated in The designation of a unit dosage form of the present invention combines (a) the unique characteristics of the antibody and the particular therapeutic or prophylactic effect achieved, and (b) such active compounds for the treatment of susceptibility in an individual. Determined by technology-specific limitations and depend directly on them.

  Note that dosage values may vary depending on the type and severity of the alleviating condition and may include single or multiple doses. For any particular subject, the specific dosage regimen should be adjusted in the course of the individual needs and the professional judgment of the person performing or directing the administration of the composition, and the administration indicated herein It is further understood that the range of amounts is exemplary only and does not limit the scope or practice of the claimed composition.

  In one embodiment, the pH is from about 5.0 to about 6.5, the antibody is from about 1 mg / ml to about 200 mg / ml, the histidine buffer is from about 1 mM to about 100 mM, and the polysorbate 80 is about 0.01 mg / ml. The antibody is administered in a formulation that is a sterile aqueous solution containing about 10 mg / ml, about 100 mM to about 400 mM trehalose, and about 0.01 mM to about 1.0 mM EDTA disodium dihydrate. Exemplary formulations include, but are not limited to, PCT / US2006 / 007551, filed on March 2, 2006, now published on September 14, 2006 as WO2006 / 096488, and PCT / US2006 / 007555, March 2006. The formulation as described on Sep. 14, 2006, which is filed on May 2, 2006 and currently published as WO 2006/096491 is included.

  In other embodiments, at a pH of about 5-6, the antibody together with sodium acetate, polysorbate 80, and sodium chloride is 5 mg / ml, more preferably about 10 mg / ml, more preferably about 15 mg / ml, much more preferably about The antibody is administered in an intravenous formulation that is a sterile aqueous solution containing 20 mg / ml. Preferably, the intravenous formulation is a sterile aqueous solution at pH 5.5 containing 5 or 10 mg / ml of antibody with 20 mM sodium acetate, 0.2 mg / ml polysorbate 80, 140 mM sodium chloride. Furthermore, solutions containing anti-CTLA4 antibodies are known in the histidine, mannitol, sucrose, trehalose, glycine, poly (ethylene) glycol, EDTA, methionine, and any combination thereof, and related fields, among other compounds. Many other compounds may be included.

  In addition to the chelating agent, the composition of the present invention may further comprise a pharmaceutically acceptable antioxidant. Suitable antioxidants include, but are not limited to, methionine, sodium thiosulfate, catalase, and platinum. For example, the composition may comprise methionine at a concentration of 1 mM to about 100 mM, specifically about 27 mM.

  In one embodiment, part of the administration is by intravenous bolus administration of the antibody formulation and the rest by infusion. For example, an intravenous injection of 0.01 mg / kg of antibody can be performed as a bolus, and the remainder of a predetermined antibody dose can be administered by intravenous injection. For example, a predetermined dose of antibody can be administered over an hour and a half to 2 hours, or 5 hours.

  With respect to a therapeutic agent, if the agent is a small molecule, for example, it may be a physiologically acceptable ester or salt, such as those associated with a physiologically acceptable cation or anion, as is well known in the art. In the form of a pharmaceutical composition.

  Formulations of the pharmaceutical compounds described herein can be prepared by any method known in the pharmaceutical art or developed in the future. In general, such methods of preparation involve associating the active ingredient with a carrier or one or more other accessory ingredients, and then molding or packaging the product, if necessary or desirable, to produce the desired single or Including the step of multiple dose units.

  Pharmaceutical compositions useful in the methods of the invention are prepared, packaged, or sold as formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, nasal, buccal, ocular, or other routes of administration. can do. Other contemplated formulations include projected nanoparticles, liposomal formulations, re-encapsulated red blood cells containing active ingredients, and immunologically based formulations.

  The pharmaceutical composition of the present invention can be prepared, packaged, or sold in large quantities as a single unit dose or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of a pharmaceutical composition that contains a predetermined amount of an active ingredient. The amount of the active ingredient is generally the same as the dosage of the active ingredient administered to the subject, or a convenient part of such a dose, eg one half or one third of such a dose. is there.

  The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in the pharmaceutical composition of the invention will depend on the route by which the composition is further administered, depending on the nature, size and condition of the subject being treated. Depending on the situation. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

  In addition to the active ingredient, the pharmaceutical composition of the present invention may further comprise one or more additional pharmaceutically active agents. Preferred intended additional agents include antiemetics, antidiarrheals, chemotherapeutic agents, cytokines and the like.

  Conventional techniques can be used to make controlled or sustained release formulations of the pharmaceutical compositions of the invention.

  Formulations of the pharmaceutical composition of the present invention suitable for oral administration include, but are not limited to, tablets, hard or soft capsules, cachets, troches, or lozenges each containing a predetermined amount of the active ingredient. It can be prepared, packaged or sold in the form of a separate solid dosage unit containing. Other formulations suitable for oral administration include, but are not limited to, powder or granule formulations, aqueous or oily suspensions, aqueous or oily solvents, or emulsions.

  As used herein, an “oily” liquid is one that contains carbon-containing liquid molecules and exhibits a lower polarity than water.

  A tablet containing the active ingredient can be made, for example, by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be mixed in a suitable apparatus, optionally with one or more binders, lubricants, additives, surfactants, and dispersing agents to provide a free-flowing active ingredient such as a powder or granule formulation Can be prepared by compression. Molded tablets can be made by molding, in a suitable device, the active ingredient, a pharmaceutically acceptable carrier, and a mixture of the liquid that is at least sufficient to wet the mixture.

  Pharmaceutically acceptable additives used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binders, and lubricants. Known dispersants include, but are not limited to, potato starch and sodium starch glycolate. Known surfactants include, but are not limited to, sodium lauryl sulfate. 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. Known binders include, but are not limited to, gelatin, acacia, pregelatinized corn starch, polyvinyl pyrrolidone, and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silicic acid, and talc.

  The tablets may be uncoated, or the tablets may be coated using known methods for delaying disintegration in the subject's gastrointestinal tract, resulting in sustained release and absorption of the active ingredient . As an example, tablets can be coated using materials such as glyceryl monostearate and glyceryl distearate. As a further example, tablets may be coated using the methods described in US Pat. Nos. 4,256,108, 4,160,452, and 4,265,874 to produce osmotic controlled release tablets. Can be formed. Tablets may further comprise sweetening agents, flavoring agents, coloring agents, preservatives, or some combination of these in order to provide a pharmaceutically refined and savory formulation.

  Physiologically degradable compositions such as gelatin can be used to make hard capsules containing the active ingredient. 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.

  Physiologically degradable compositions such as gelatin can be used to make soft gelatin capsules containing the active ingredient. Such soft capsules contain active ingredients that can be mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.

  Liquid formulations of the pharmaceutical composition of the present invention suitable for oral administration should be prepared, packaged and sold in liquid form or in dry form intended to dissolve in water or other suitable medium prior to use. Can do.

  Liquid suspensions can be prepared using conventional methods of suspending the active ingredients in an aqueous or oily medium. Aqueous media include, for example, water and isotonic saline. Oily media include, for example, tonsils, oily esters, ethyl alcohol, peanut oil, olive oil, vegetable oils such as sesame oil and coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions further include, but are not limited to, suspending, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. One or more additional components may be included. The oily suspension may further contain a thickener. Known suspending agents include, but are not limited to, sorbitol syrup, hardened edible fat, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally occurring phospholipids such as lecithin, fatty acids, long chain fatty alcohols, partial esters derived from fatty acids and hexitol, or fatty acids and hexitol anhydrous. There are condensates of partial esters and alkylene oxides derived from the products (for example, polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifiers include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para-hydroxybenzoate, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known oily suspension thickeners include, for example, beeswax, hard paraffin, and cetyl alcohol.

  A solution of the active ingredient dissolved in an aqueous or oily solvent can be prepared in substantially the same manner as a liquid suspension, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. It is. It will be understood that solutions of the pharmaceutical composition of the present invention may include each of the components described with respect to the liquid suspension, and that the suspending agent does not necessarily help dissolve the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, tonsil oil, oily esters, ethyl alcohol, peanut oil, olive oil, vegetable oils such as sesame oil and coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

  The powder and granule preparation of the pharmaceutical preparation of the present invention can be prepared using known methods. Such formulations can be administered directly to a subject and used to form an aqueous or oily suspension, for example by forming a tablet, filling a capsule, or adding an aqueous or oily medium thereto Alternatively, a liquid preparation can be prepared. Each of these formulations may further contain one or more dispersing or wetting agents, suspending agents and preserving agents. Additional additives such as fillers and sweetening, flavoring, or coloring agents can also be included in these formulations.

  The pharmaceutical composition of the present invention can also be prepared, packaged, or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions are further combined with emulsifiers such as naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phospholipids such as soybean or lecithin phospholipids, fatty acids such as sorbitan monooleate and hexitol anhydride combinations. One or more condensates of such partial esters and ethylene oxide, such as derived or partial esters, polyoxyethylene sorbitan monooleate may be included. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

  The pharmaceutical composition of the present invention can be prepared, packaged, or sold in a formulation suitable for rectal administration. Such compositions may be in the form of, for example, suppositories, retention enema preparations, and solutions for rectal or colonic irrigation.

  Mix the active ingredient with a pharmaceutically acceptable non-irritating additive that is solid at normal room temperature (ie, about 20 ° C.) and liquid at the subject's rectal temperature (ie, about 37 ° C. in healthy subjects). By doing so, a suppository can be prepared. Suitable pharmaceutically acceptable additives include, but are not limited to, cocoa butter, polyethylene glycol, and various glycerides. Suppositories may further contain a variety of additional ingredients including, but not limited to, antioxidants and preservatives.

  Retentive enema preparations or solutions for rectal or colonic irrigation can be made by mixing the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema formulations can be administered and packaged within a delivery device that is adapted to the subject's rectal anatomy. Enema formulations may further comprise a variety of additional ingredients including, but not limited to, antioxidants and preservatives.

  The pharmaceutical composition of the present invention can be prepared, packaged or sold in a formulation suitable for vaginal administration. Such compositions may be in the form of, for example, suppositories, osmotic or covering vaginal inserts such as tampons, press injections, or gels or creams or solutions for vaginal cleansing.

  Methods for infiltrating or coating a substance with a chemical composition are known in the art and include, but are not limited to, methods for depositing or bonding a chemical composition onto a surface. A method of incorporating a chemical composition into the structure of a substance during the synthesis of the substance (ie, a physiologically degradable substance), and an aqueous or oily solution or suspension, with or without subsequent drying There is a method of absorbing the water in the absorbent material.

  Injectable preparations or vaginal cleansing solutions can be prepared by mixing the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, infusion formulations can be administered and packaged within a delivery device adapted to the subject's vaginal anatomy. Injectable formulations may further include a variety of additional ingredients including, but not limited to, antioxidants, antibiotics, antifungal agents, and preservatives.

  As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physically tearing the tissue of interest and administering the pharmaceutical composition through a tear in the tissue. Thus, parenteral administration includes, but is not limited to, injection of the composition, application of the composition through a surgical incision, application of the composition through a non-surgical wound that penetrates tissue, etc. Administration is included. Specifically, parenteral administration is intended to include, but is not limited to, transdermal, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

  Formulations of pharmaceutical compositions suitable for parenteral administration comprise the active ingredient in admixture with a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline. Such formulations can be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable preparations can be prepared, packaged, or sold in unit dosage forms such as ampoules or multiple dose containers containing preservatives. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous solvents, pastes, and implantable sustained release or biodegradable formulations discussed below. . Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is dissolved in an appropriate vehicle (eg, sterile pyrogen-free water) and then dried for parenteral administration of the dissolved composition ( Ie in powder or granule form.

  The compositions of the present invention can be administered by a variety of methods known in the art. The route of administration and / or form will vary depending on the desired outcome. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Numerous methods for preparing such formulations are patented or generally known to those skilled in the art. Many methods for preparing such formulations are described, for example, in “Sustained and Controlled Release Drug Delivery Systems”, J. Org. R. Edited by Robinson, Marcel Dekker, Inc. , New York (1978). The pharmaceutical composition is preferably manufactured under GMP conditions.

  The pharmaceutical compositions can be prepared, packaged, or sold in the form of an aqueous or oily injectable sterile suspension or solution. This suspension or solution may be formulated according to known techniques and may contain, in addition to the active ingredient, further ingredients such as dispersants, wetting agents and suspending agents described herein. Such injectable sterile formulations can be prepared using non-toxic diluents or solvents that are acceptable for parenteral administration, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to Ringer's solution, isotonic sodium chloride solution, and non-volatile oils such as synthetic mono- or diglycerides. Other useful formulations that can be administered parenterally include those that contain the active ingredient in microcrystalline form, in a liposomal formulation, or as a component of a biodegradable polymer system. Sustained release or implantable compositions may include pharmaceutically acceptable polymers or hydrophobic substances such as emulsions, ion exchange resins, sparingly soluble polymers and sparingly soluble salts.

  Formulations suitable for topical administration include, but are not limited to, liquids such as rubs, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments and pastes, solutions or suspensions. Or there is a semi-liquid formulation. Formulations that can be administered topically may contain, for example, 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 in the solvent. . Formulations for topical administration may further comprise one or more additional ingredients as described herein.

  The pharmaceutical composition of the present invention can be prepared, packaged, or sold as a preparation suitable for pulmonary administration via the oral cavity. Such formulations may comprise dry particles comprising the active ingredient and having a diameter of about 0.5 to about 7 nm, preferably about 1 to about 6 nm. Such compositions advantageously use a device that includes a dry powder reservoir that can disperse the powder toward the propellant stream, or dissolve in the low boiling propellant in a closed container. Or in the form of a dry powder for administration using a self-propelling solvent / powder formulation containing the active ingredient to be suspended. Preferably, such powder comprises particles that are at least 98% by weight greater than 0.5 nm in diameter and at least 95% by number of particles less than 7 nm in diameter. More preferably, at least 95% of the particles by weight are greater than 1 nm in diameter, and at least 90% of the particles by number of particles are less than 6 nm in diameter. The dry powder composition preferably comprises a solid fine powder diluent such as sugar and is conveniently provided in unit dosage form.

  Low boiling propellants generally include liquid propellants having a boiling point of 65 ° F. at atmospheric pressure. In general, the propellant may account for 50 to 99.9% (w / w) of the composition and the active ingredient may account for 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional components such as liquid nonionic or solid anionic surfactants and solid diluents (preferably having a particle size comparable to the particles containing the active ingredient).

  The pharmaceutical composition of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of liquid or suspension droplets. Such compositions can be sterile and can be prepared, packaged, or sold as aqueous or diluted alcoholic solvents or suspensions containing the active ingredients, conveniently in any spraying or atomizing device. Can be used to administer. Such formulations may further comprise one or more additional ingredients including, but not limited to, flavoring agents such as sodium saccharin, volatile oils, buffering agents, surfactants, or preservatives such as methyl hydroxybenzoate. Good. The droplets provided by this route of administration preferably have an average diameter of about 0.1 to about 200 nm.

  The formulations described herein useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions of the invention.

  Another formulation suitable for intranasal administration is a crude powder containing the active ingredient and having an average particle of about 0.2-500 μm. Such formulations are administered in a manner that provides nasal inhalation, ie, by rapid inhalation through the nasal passage from a container of powder held near the nostril.

  Formulations suitable for nasal administration may comprise, for example, from a minimum of about 0.1% (w / w) to a maximum of 100% (w / w) active ingredient, as further described herein. One or more additional components may be included.

  The pharmaceutical composition of the present invention can be prepared, packaged or sold as a preparation suitable for buccal administration. Such formulations may be, for example, in the form of tablets or lozenges made using conventional methods and may contain, for example, 0.1% to 20% (w / w) active ingredient, The balance includes compositions that are soluble or degradable in the mouth, and may include one or more additional ingredients as described herein. Alternatively, formulations suitable for buccal administration may comprise a powder containing the active ingredient or an aerosolized or atomized solvent or suspension. Such a powdered or aerosolized formulation, when dispersed, preferably has an average particle or droplet size of about 0.1 to about 200 nm, and further includes one or more additional ingredients as described herein. May be included.

  The pharmaceutical composition of the present invention can be prepared, packaged, or sold as a formulation suitable for ocular administration. Such a preparation may be, for example, in the form of eye drops containing, for example, 0.1 to 1.0% (w / w) of a solution or suspension of the active ingredient in an aqueous or oily liquid carrier. Such eye drops may further comprise a buffer, salt, or one or more additional ingredients as described herein. Other useful formulations that can be administered to the eye include those that contain the active ingredient in the form of microcrystals or in a liposomal formulation.

  As used herein, “further ingredients” include, but are not limited to, additives; surfactants; dispersants; inert diluents; granulating and disintegrating agents; binders; lubricants; Colorants; preservatives; physiologically degradable compositions such as gelatin; aqueous media and solvents; oily media and solvents; suspending agents; dispersants or wetting agents; emulsifiers; Salts, thickeners, fillers, emulsifiers, antioxidants, antibiotics, antifungal agents, stabilizers, and one or more of pharmaceutically acceptable polymers or hydrophobic substances. Other “further ingredients” that can be included in the pharmaceutical compositions of the present invention are known in the art, eg, “Remington's Pharmaceutical Sciences”, edited by Genaro, Mack, which is incorporated herein by reference. Publishing Co. , Easton, Pennsylvania (1985).

  In one embodiment of the invention, a composition comprising CP-675,206 comprises 20 mM histidine buffer, pH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0. Contains a sterile solution containing 1 mg / ml EDTA disodium hydrate. In one embodiment, CP-675,206 is packed into a clear glass vial with a rubber stopper and an aluminum seal. In another aspect, the vial contains about 20 mg / ml CP-675,206 and is nominally filled with 400 mg per vial.

  The anti-CTLA4 / therapeutic agent active ingredient combination of the present invention can be administered to animals, preferably humans. The exact dosage of each active ingredient will vary depending on any number of factors including, but not limited to, the type of animal, the type of disease state being treated, the age of the animal and the route of administration.

  Anti-CTLA4 antibody can be administered to animals several times a day, or less frequently, once a day, once a week, once every two weeks, once a month, etc. Or it can be administered less frequently, such as once every few months, or even less than once a year. The frequency of administration will be readily apparent to those skilled in the art and will depend on any number of factors including, but not limited to, the type and severity of the disease being treated, the type and age of the animal.

  The therapeutic agent, preferably a chemotherapeutic agent, can be administered to the animal several times a day, or once a day, once a week, once every two weeks, a month It can also be administered less frequently, such as once a day, or less frequently, such as once every few months, or even less than once a year. The frequency of administration will be readily apparent to those skilled in the art and will depend on any number of factors including, but not limited to, the type and severity of the disease being treated, the type and age of the animal.

  The antibody and therapeutic agent can be co-administered in that they can be administered separately, on different days or at different times of the day, or at the same time or on the same day. Thus, simultaneous administration of an antibody and therapeutic agent such that administration of the two agents results in a therapeutic benefit to the patient that is detectably greater than administration of either agent in the absence of the other. Includes any temporary combination of administration.

  The antibody-therapeutic agent combinations of the present invention can be co-administered with a number of other compounds, especially among other anti-hormonal therapeutic agents, cytokines, chemotherapy and / or antiviral agents. . Alternatively, the compound (s) can be administered 1 hour, 1 day, 1 week, 1 month, or even more before the antibody-therapeutic agent combination, or any permutation thereof. Furthermore, preferably 1 hour, 1 day, 1 week after irradiation, stem cell transplantation, administration of any therapeutic agent (eg, cytokine, chemotherapeutic compound, etc.), or any permutation thereof, Alternatively or even later, the compound (s) can be administered. The frequency and method of treatment will be readily apparent to those of skill in the art and include, but are not limited to, the type and severity of the disease being treated, the age and health of the animal, the nature of the compound or compounds being administered, various It depends on any number of factors, such as the route of administration of the compound.

VI. Kits The invention comprises a therapeutically effective amount of a human anti-CTLA4 antibody and a therapeutically effective amount of a therapeutic agent of the invention, together with instructions describing the use of the applicator and combinations thereof to perform the methods of the invention Includes various kits including Exemplary kits are described below, but other useful kit contents will be apparent to those of skill in the art in light of the present disclosure. Each of these kits is included within the scope of the present invention.

  The present invention includes a kit for the treatment of breast cancer in a patient in need thereof. The kit includes a human anti-CTLA4 antibody of the present invention and at least one therapeutic agent. Inhibitors include, but are not limited to, chemotherapeutic agents, antibodies, cytokines, vaccines, immunomodulators, among many others. The kit further includes an applicator for administering the components of the kit to the patient, including but not limited to a syringe. In addition, the kit includes instructions that provide appropriate information about the use of the kit to treat the patient's breast cancer.

  More preferably, the kit comprises antibodies 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 at least one anti-CTLA4 antibody selected from antibodies having the heavy and light chain amino acid sequences of ipilimumab, more preferably the antibody comprises: Antibodies having the heavy and light chain amino acid sequences of antibodies 4.13.1, 11.2.1 (CP-675,206), and ipilimumab (MDX-010). Preferably, the antibody is an antibody having heavy and light chain sequences of 11.2.1 (CP-675,206). More preferably, the anti-CTLA4 antibody is CP-675,206 or ipilimumab. Most preferably, the antibody is CP-675,206.

  The kit can include any number of additional therapeutic agents for treating cancer. Such agents are indicated above and include, among others, chemotherapeutic compounds, cancer vaccines, signaling inhibitors, agents useful in treating abnormal cell growth or cancer, IGF There are antibodies or other ligands and cytokines that inhibit tumor growth by binding to -1R.

  The present invention also provides a human anti-CTLA4 antibody in a therapeutically effective amount (eg, an amount greater than 10 mg / kg, or at least 15 mg / kg, or 15 mg / kg) and a therapeutically effective amount of a second therapeutic effect. It also relates to an article of manufacture containing the substance (eg, a dosage form compatible with iv administration). In certain embodiments, the article of manufacture includes one or more containers containing human anti-CTLA4 antibodies, therapeutic agents, and indications and / or instructions for use in cancer treatment.

  In one embodiment, the therapeutic agent is a hormone therapeutic agent, taxane, heat shock protein, topoisomerase inhibitor, hormone therapeutic agent (eg, leuprolide), chemotherapeutic compound, vinca alkaloid, platinum compound, cancer vaccine, Tumor-specific antigens, angiogenesis inhibitors, 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 at least one agent selected from cytokines.

  The kit can include any number of additional therapeutic agents for treating cancer. Such agents are indicated above and include, among others, chemotherapeutic compounds, cancer vaccines, signaling inhibitors, agents useful in treating abnormal cell growth or cancer, IGF There are antibodies or other ligands that inhibit tumor growth by binding to -1R, and cytokines, and palliative drugs (eg, antidiarrheals, antiemetics, etc.).

  In another embodiment of the invention, the kit is for breast cancer treatment. The kit includes an anti-CTLA4 antibody and a taxane. In one aspect, the taxane is docetaxel or paclitaxel. In other embodiments, the treatment is a first line therapy to treat locally advanced or metastatic triple receptor negative breast cancer patients.

  In one embodiment, the kit is for ovarian cancer treatment. In one aspect, the kit includes an anti-CTLA4 antibody and a therapeutic agent, wherein the therapeutic agent is paclitaxel. In other embodiments, the kit further comprises carboplatin. In yet another embodiment, the kit is for first line treatment of advanced ovarian cancer. In other embodiments, the kit is for second line treatment of patients who have deteriorated after previous paclitaxel based therapy.

  In an embodiment of the invention, the kit is for treatment of non-small cell lung cancer. In one embodiment, the kit comprises an anti-CTLA4 antibody and a chemotherapeutic agent and the therapeutic agent is platin (eg, carboplatin, paclitaxel (TAXOL)), docetaxel (TAXOTERE), sunitinib (SU11248), erlotinib (TARCEVA), bevacizumab (AVASTIN), pemetrexed (ALIMTA), and PF03512676 (CpG-7909).

  In one embodiment, the kit is for first line treatment of locally advanced stage IIIb or metastatic stage IV NSCLC and the kit comprises an anti-CTLA4 antibody and platin. In other embodiments, the kit comprises carboplatin and paclitaxel. In other embodiments, the kit comprises an antibody and bevacizumab. In a further embodiment, the kit comprises an antibody and PF03512676. In other embodiments of the invention, the kit comprises an antibody and sunitinib.

  In one embodiment, the kit is for second line treatment of locally advanced stage IIIb or metastatic stage IV NSCLC after failure of platinum-based therapy. In one embodiment, the kit comprises an anti-CTLA4 antibody and docetaxel. In other embodiments, the kit comprises an antibody and erlotinib. In yet other embodiments, the kit comprises an antibody and pemetrexed. In yet other embodiments, the kit comprises an anti-CTLA4 antibody.

  In another embodiment of the invention, the kit is for third-line treatment of locally advanced stage IIIb or metastatic stage IV NSCLC. The kit includes an effective amount of anti-CTLA4 antibody. In one aspect, the kit is for cancer treatment after previously failing platinum-based chemotherapy and EGFR inhibition-based therapy.

  In one embodiment, the kit is for the treatment of pancreatic cancer. The kit includes an anti-CTLA4 antibody and a therapeutic agent, wherein the agent is gemcitabine. In one aspect, the treatment is first line therapy for locally advanced and unresectable stage II or III of the pancreas or metastatic stage IV adenocarcinoma.

  In one embodiment, the kit is for the treatment of melanoma and comprises an effective amount of an anti-CTLA4 antibody and an effective amount of IFNα. In one aspect, the treatment is adjuvant therapy for stage II / III melanoma.

  In an embodiment of the invention, the kit is for colorectal cancer treatment. In one aspect, the kit comprises an effective amount of an anti-CTLA4 antibody and an effective amount of fluorouracil, leucovorin and oxaliplatin (FOLFOX), respectively. In other embodiments, the kit comprises an effective amount of an anti-CTLA4 antibody, fluorouracil, leucovorin and irinotecan (FOLFIRI). In one aspect, the treatment is first line therapy for metastatic CRC. In other embodiments, the treatment is adjuvant therapy for stage III colon cancer in a patient who has undergone resection of the primary tumor.

  In other embodiments, the kit is for CRC treatment and comprises an effective amount of anti-CTLA4 antibody and an effective amount of capecitabine (XELODA). In one aspect, the treatment is a first line therapy for patients who are intolerant to a therapy comprising oxaliplatin (ELOXATIN) or irinotecan (CAMPTOSAR).

  The invention will now be described in more detail with reference to the following experimental examples. These examples are provided for illustrative purposes only, and are not limiting unless otherwise specified. Accordingly, the present invention should in no way be construed as limited to the following examples, but rather is intended to encompass any and all modifications that may become apparent as a result of the teaching provided herein. Should be considered.

CP-675,206 in combination with rituximab in first-line treatment of low-grade non-Hodgkin lymphoma
Patients with low-grade non-Hodgkin lymphoma are treated with CP-675,206 and rituximab. Low-grade non-Hodgkin's lymphoma (NHL) is a slow-growing type of lymphoma, including those previously referred to as low-grade and some types of medium-grade NHL in the Working Formulation category. For non-Hodgkin lymphoma (NHL) with at least one lesion that can be accurately measured in two dimensions and its size is ≧ 2 cm × 1 cm on a conventional CT scan or ≧ 1 cm × 1 cm on a helical CT scan Standard Rituximab (RITUXAN) antibody therapy is performed according to established protocols.

  In addition, the patient is given a single IV infusion of CP-675,206 (100 mL / hr) at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. After 28 days, the dose of CP-675,206 was gradually increased, ie treatment was repeated at 6 mg / kg, 10 mg / kg and 15 mg / kg, and every 28 days thereafter, intolerant toxicity did not occur or the disease If not worse, repeat up to 12 cycles. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

Rituximab is administered by intravenous infusion once a week at about 375 mg / m ² and is administered about 4 or 8 times. More preferably, rituximab is administered on the first day of each cycle of chemotherapy.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes before injecting either antibody. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  Rituximab and anti-CTLA4 antibody are administered once or repeatedly, either sequentially or simultaneously as defined.

  Following combination treatment with rituximab and anti-CTLA4 antibody, anti-CTLA4 antibody is administered as a single agent (SA) therapy as described above for combination therapy.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, the US East Coast Cancer Clinical Trials Group General Status (ECOG PS), vital signs, and body weight are assessed prior to administration, and vital signs may be repeated after administration if clinically required. it can. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose (sodium, urea, uric acid)), Urinalysis (blood, protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4 , Serum Ig level).

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with rituximab in second-line treatment of high-grade non-Hodgkin lymphoma
High-grade and CHOP-R with at least one lesion that can be accurately measured in two dimensions and whose size is ≧ 2 cm × 1 cm on a conventional CT scan or ≧ 1 cm × 1 cm on a helical CT scan Patients suffering from refractory NHL receive standard rituximab antibody therapy according to established protocols.

  In addition, the patient is given a single IV infusion (100 mL / hr) of CP-675,206 as described herein at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. Incremental doses of anti-CTLA4 antibody after 28 days, ie, repeat treatment at 6 mg / kg, 10 mg / kg and 15 mg / kg, then no intolerant toxicity or disease progression every 28 days In some cases, a maximum of 12 cycles are repeated. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months. The patient is administered rituximab according to art-recognized methods of administration.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  Rituximab (RITUXAN) and anti-CTLA4 antibody are administered once or repeatedly, either sequentially or simultaneously as defined.

  Following combination treatment with RITUXAN and anti-CTLA4 antibody, anti-CTLA4 antibody is administered as described above.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with 5-fluorouracil or capecitabine in adjuvant or first line treatment for colorectal cancer
For colorectal cancer (CRC) with at least one lesion that can be accurately measured in two dimensions and whose size is ≧ 2 cm × 1 cm on a conventional CT scan or ≧ 1 cm × 1 cm on a helical CT scan Patients who are affected and intolerant to oxaliplatin (ELOXATIN) or irinotecan (CAMPTOSAR) receive standard chemotherapy using 5FU (fluorouracil) or XELODA (capecitabine) according to established protocols.

  In addition, the patient is given a single IV infusion (100 mL / hr) of CP-675,206 as described herein at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. Incremental doses of anti-CTLA4 antibody after 28 days, ie, repeat treatment at 6 mg / kg, 10 mg / kg and 15 mg / kg, then no intolerant toxicity or disease progression every 28 days In some cases, a maximum of 12 cycles are repeated. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  Capecitabine for second line therapy or 5-fluorouracil for adjuvant therapy is administered once or repeatedly with CP-675,206, either sequentially or simultaneously, as defined. Capecitabine and fluorouracil are administered according to well-known protocols, such as those disclosed in the FDA approval label for each compound.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with FOLFOX in adjuvant or first line treatment for colorectal cancer
A colon with at least one lesion that can be accurately measured in two dimensions after surgery / radiotherapy and whose size is ≧ 2 cm × 1 cm on a conventional CT scan or ≧ 1 cm × 1 cm on a helical CT scan Patients suffering from rectal cancer (CRC) receive standard chemotherapy using FOLOX (fluorouracil, leucovorin and oxaliplatin) according to established protocols.

  Further, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. Incremental doses of anti-CTLA4 antibody after 28 days, ie, repeat treatment at 6 mg / kg, 10 mg / kg and 15 mg / kg, then no intolerant toxicity or disease progression every 28 days In some cases, a maximum of 12 cycles are repeated. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

FOLFOX or FOLFIRI therapy is performed according to standard protocols. Briefly, with FOLFOX4, each chemotherapy cycle consists of a 2-hour infusion of 85 mg / m ² oxaliplatin (ELOXATIN, Sanofi) on day 1 followed by 200 mg / m ² leucovorin on days 1 and 2. Includes a ² hour infusion followed by a bolus dose of 400 mg / m ² fluorouracil on days 1 and 2, followed by a 22 hour infusion of 600 mg / m ² fluorouracil administered over 2 consecutive days (also called the De Gramont plan). Chemotherapy is repeated every 2 weeks.

In an exemplary dosing regimen, FOLFIRI is a 90 minute infusion of 180 mg / m ² irinotecan on day 1 and a 2 hour infusion of 400 mg / m ² folinic acid (leucovorin) on day 1 and 400 after leucovorin on day 1. IV bolus administration of ˜500 mg / m ² fluorouracil, i. v. Dosing is administered as 2400-3000 mg / m ² fluorouracil administered. This chemotherapy cycle is repeated every 2 weeks.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  FOLFOX therapy is performed once or repeatedly, sequentially or simultaneously with anti-CTLA4 antibody, as defined.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 and gemcitabine for the treatment of pancreatic cancer After surgery / radiotherapy, if any, can be accurately measured in two dimensions, its size is ≧ 2 cm × 1 cm on a conventional CT scan, or helical CT Patients suffering from pancreatic cancer with at least one lesion that is ≧ 1 cm × 1 cm on a scan are given standard chemotherapy including gemcitabine (eg, GEMZAR) according to established protocols.

  In addition, the patient is given a single IV infusion of an anti-CTLA4 antibody as described herein at a dose of at least about 10 mg / kg, preferably about 15 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. If desired, the treatment is repeated with increasing doses of anti-CTLA4 antibody after 28 days and then repeated every 28 days for up to 12 cycles if intolerant toxicity does not occur or the disease does not worsen . Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

Gemcitabine is administered according to standard protocols. More specifically, intravenous infusion over 30 minutes at a dose of 1000 mg / m ² once a week for a maximum of 7 weeks (or until it is necessary to reduce the dose or stop it because of toxicity) Then, gemcitabine (GEMZAR, Lilly) is administered by suspending treatment for 1 week. Subsequent cycles should consist of infusions once every week for 3 weeks, of each 4 weeks. CP-675,206 is administered after the first gemcitabine cycle (7 weeks of treatment and 1 week of rest), followed by once every 3 weeks.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  Where appropriate, 3-6 subjects per cohort are used to titrate antibody doses using an accelerated dose regimen that utilizes a dose doubling schedule. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with imatinib mesylate in first line therapy for chronic myelogenous leukemia
Patients with chronic myelogenous leukemia (CML) receive standard chemotherapy using imatinib mesylate (GLEEVEC) according to established protocols.

  Further, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. Incremental doses of anti-CTLA4 antibody after 28 days, ie, repeat treatment at 6 mg / kg, 10 mg / kg and 15 mg / kg, then no intolerant toxicity or disease progression every 28 days In some cases, a maximum of 12 cycles are repeated. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

  Imatinib mesylate (GLEEVEC, Novartis) is administered daily at about 400 mg / day for chronic phase CML patients and at 600 mg / day for adult patients in accelerated or blast phase. Imatinib treatment may be continued as long as there is no worsening of the disease or unacceptable toxicity.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  Imatinib mesylate is administered once or repeatedly sequentially or simultaneously with the anti-CTLA4 antibody as defined.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with imatinib mesylate (GLEEVEC) in first line therapy for chronic lymphocytic leukemia
Patients with chronic lymphocytic leukemia (CLL) receive standard chemotherapy using imatinib mesylate (GLEEVEC) according to established protocols.

  Further, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. Incremental doses of anti-CTLA4 antibody after 28 days, ie, repeat treatment at 6 mg / kg, 10 mg / kg and 15 mg / kg, then no intolerant toxicity or disease progression every 28 days In some cases, a maximum of 12 cycles are repeated. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months. Imatinib mesylate (GLEVEVEC, Novartis) may be administered daily at about 400 mg / day or 600 mg / day and continued as long as there is no worsening of the disease or unacceptable toxicity.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  GLEEVEC is administered once or repeatedly, either sequentially or simultaneously with anti-CTLA4 antibody, as defined.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with carboplatin and paclitaxel in first-line therapy for advanced ovarian cancer
Patients suffering from advanced cancer of the ovary are given standard chemotherapy using carboplatin and paclitaxel according to established protocols.

  Further, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 3 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. Incremental doses of anti-CTLA4 antibody after 28 days, ie, repeat treatment at 6 mg / kg, 10 mg / kg and 15 mg / kg, then no intolerant toxicity or disease progression every 28 days In some cases, a maximum of 12 cycles are repeated. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

An exemplary dosing regimen is 175 mg / m ² every 3 weeks for 90 minutes. v. Administer paclitaxel by infusion, followed by carboplatin (area under time-blood concentration curve [AUC] 5) i. v. Administer.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  With 3-6 subjects per cohort, doses are gradually increased using an accelerated dose regimen that utilizes a dose doubling plan. Within each new cohort, no waiting time between subjects is required. Subsequent cohorts may not begin until the first subject at the current dose level is observed for 21 days and the subsequent subject is observed for 14 days.

  The combination of carboplatin and paclitaxel is administered once or repeatedly sequentially or simultaneously with the anti-CTLA4 antibody as defined.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with carboplatin and paclitaxel and bevacizumab, PF03512676, or sunitinib in first line therapy for non-small cell lung cancer
Patients suffering from locally advanced stage IIIb or metastatic stage IV NSCLC receive standard chemotherapy using carboplatin and paclitaxel according to established protocols.

  In addition, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 15 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. The treatment is repeated after 28 days and is repeated approximately 12 cycles if intolerant toxicity does not occur or the disease does not worsen. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

  In addition, the patient is administered bevacizumab (AVASTIN), PF03512676, or sunitinib according to established protocols. Bevacizumab is about 5 mg / kg i. v. Infusion can be administered every 14 days until disease worsening is detected. Sunitinib can be administered as a 50 mg oral dose once a day with a 4-week treatment followed by a 2-week rest schedule. Sunitinib may be administered in a meal or in a fasted state. A dosage increase of 12.5 mg is recommended based on individual safety and tolerability. Exemplary carboplatin and paclitaxel administration methods are as indicated above.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  The combination of carboplatin and paclitaxel is administered once or repeatedly sequentially or simultaneously with the anti-CTLA4 antibody as defined. Similarly, bevacizumab, sunitinib, or PF03512676 is administered once or repeatedly, either sequentially or simultaneously with anti-CTLA4-carboplatin-paclitaxel as indicated.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with docetaxel, erlotinib or pemetrexed in second line therapy for non-small cell lung cancer
Patients with locally advanced stage IIIb or metastatic stage IV NSCLC who have previously failed platinum-based chemotherapy may be treated according to established protocols according to docetaxel (TAXOTERE), erlotinib (TARCEVA), Or standard chemotherapy using one of pemetrexed (ALIMTA).

  In addition, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 15 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. The treatment is repeated after 28 days and is repeated approximately 12 cycles if intolerant toxicity does not occur or the disease does not worsen. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

Docetaxel (TAXOTERE, Sanofi-Aventis) is approximately 75 mg / m ² , i. v. Administer every 3 weeks by infusion. Erlotinib (TARCEVA, OSI Pharms.) Is administered as a dose of about 150 mg once a day at least 1 or 2 hours after food intake. Treatment should continue until disease worsens or unacceptable toxicity occurs. Pemetrexed (ALIMTA, Lilly) is administered i.d. for 10 minutes at a dose of about 500 mg / m ² . v. As an infusion, it is administered on the first day of each cycle of 21 days.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  Docetaxel, erlotinib or pemetrexed is administered once or repeatedly, either sequentially or simultaneously with the anti-CTLA4 antibody, as defined.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

CP-675,206 in combination with platinum-based chemotherapy in the treatment of non-small cell lung cancer
Patients with locally advanced stage IIIb (with leaching) or metastatic stage IV NSCLC who have previously responded to first-line chemotherapy with platinum-based chemotherapy but remain stable CP-675,206 is administered at least about 3 weeks after failure of one selected platinum-based therapy but not more than about 6 weeks.

  In addition, the patient is given a single IV infusion (100 mL / hour) of the anti-CTLA4 antibody described herein at a dose of about 15 mg / kg. Administer prophylactic antiemetics and antidiarrheals as appropriate. The treatment is repeated after 28 days and is repeated approximately 12 cycles if intolerant toxicity does not occur or the disease does not worsen. Preferably, CP-675,206 is administered at least about 10 mg / kg every 3 weeks for 4 cycles and thereafter every 3 months.

  Preferably, the patient is pre-medicated with an antihistamine (H1) at least 30 minutes prior to infusion of anti-CTLA4. Premedication is recommended but not required.

  Docetaxel, erlotinib or pemetrexed is administered once or repeatedly, either sequentially or simultaneously with the anti-CTLA4 antibody, as defined.

  CP-675,206 is provided in clear 20 ml glass vials with rubber stoppers and aluminum seals. Each vial is a sterile aqueous solution containing 20 mM histidine buffer, PH 5.5, 84 mg / ml trehalose dihydrate, 0.2 mg / ml polysorbate 80, and 0.1 mg / ml disodium EDTA dihydrate. Contains 20 mg / ml of CP-675,206 (nominally 400 mg filled per vial).

  For all patients, ECOG general status, vital signs, and body weight are assessed pre-dose, and vital signs can be repeated after administration if clinically required. A physical examination (including ophthalmic evaluation and signs of autoimmunity) is performed on day 1. Blood test panel (hematocrit, RBC count, WBC count, leukocyte fraction), chemical test (alkaline phosphatase, calcium, chloride, GGT, LDH, magnesium, phosphorus, random glucose, sodium, urea, uric acid), urine test (blood , Protein), other tests (activated partial thromboplastin time [APTT], prothrombin time (PT), autoantibody panel, C-reactive protein, TSH, T3, T4, amylase, lipase, serum C3, C4, serum Ig levels A sample for) is obtained.

  Baseline human anti-human antibody (HAHA) titers are determined and pharmacokinetic (PK) analysis specimens are obtained prior to administration.

  The following endpoints are measured: PK parameters, HAHA, response rate and progression free period. Time to progression and overall survival are calculated using Kaplan-Meier aggressive limit method.

Natural history of diarrhea associated with CTLA4 blockade by anti-CTLA4 antibodies Diarrhea resulting from immune activation has been associated with CTLA4 blockade. For example, in stage IV melanoma patients receiving ipilimumab (MDX-010), some patients developed third-quarter autoimmune enterocolitis and severe diarrhea (Attia et al., 2005). Year). In a phase I study in which a single dose of CP-675,206 was administered to solid cancer patients (n = 39) at a maximum dose of 15 mg / kg, 9 cases of diarrhea were reported, including 3 cases of the third degree ( Ribas et al., 2005). In a large phase I / II study, the incidence and severity of diarrhea was evaluated in patients receiving CP-675,206.

  An open-label phase I / II study of CP-675,206 was conducted in patients with stage III (unresectable) or stage IV melanoma with ECOG PS ≦ 1. Diarrhea was evaluated in patients treated with Phase II administration: 10 mg / kg for Phase I, once a month (Q1M) (n = 22), or 10 mg / kg Q1M for Phase II (n = 44) or 15 mg / kg once every 3 months (Q3M) (n = 45).

  Median 3.5 times (range, 1-18 times) at 10 mg / kg Q1M (10Q1M) in Phase I, 3 times (range, 1-26 times) at 10 mg / kg Q1M in Phase II, and One dose (range, 1-9) of 15 mg / kg Q3M (15Q3M) was performed with 100% dose compliance. Treatment-related diarrhea was reported in 43 (39%) of 111 patients, and third-degree diarrhea occurred in 14 (13%) patients. One patient had a fourth degree colitis and a colectomy was performed. Diarrhea (of all frequencies) occurred at a similar frequency in each treatment group. However, treatment-related third-degree diarrhea is compared to 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. Happened in 8% of patients treated with 15 mg / kg Q3M. Of the 9 patients who responded objectively, 8 experienced diarrhea (3 of which were third degree). Most cases (65%) have mild to moderate severity with a median time to onset of 51 days (range, 1-583 days) and 8 days (range, 1-5) 182). More than half of the patients who reported severe diarrhea were treated with steroids.

  Diarrhea associated with CP-675,206 was primarily mild to moderate in severity and was temporary and manageable. Furthermore, 15 mg / kg Q3M may be more tolerated than 10 mg / kg Q1M.

Survival of patients with metastatic melanoma treated with anti-CTLA4 monoclonal antibody CP-675,206 in a phase I / II study CP-675,206 has shown clinical activity in patients with metastatic melanoma. In the single-dose phase I study above, prolonged survival was also observed in patients with no objective tumor response.

  A multi-dose phase I / II study was performed in patients with histologically confirmed stage IIIc (unresectable) or stage IV recurrent metastatic melanoma and ECOG PS ≦ 1 (N = 119) It was. The study included a Phase I open-label, multiple-dose study (3, 6, and 10 mg / kg) and a phase I expansion cohort of HLA-A2.1 + patients (10 mg / kg once a month [10Q1M] ), Followed by a phase II open-label study consisting of two dosing methods: 10 mg / kg Q1M and 15 mg / kg every 3 months (15Q3M). The primary endpoint was safety in Phase I, immune monitoring in the expanded cohort, and response in Phase II. Survival was analyzed as a secondary endpoint.

  In the phase I study, the Kaplan-Meier estimate for median overall survival was 17.6 months for all treatment groups (n = 28). In the phase II study, the median survival was 10.3 months in the 10 mg / kg treatment group and 11.0 months in the 15 mg / kg treatment group. Regardless of whether the patient responded or not, the survival results were good compared to the historic median survival of 7 months.

  Patients who participated in the CP-675,206 multi-dose trial showed longer survival than expected in historical controls.

Comparison of CP-675,206 anti-CTLA4 monoclonal antibody dose and dosing schedule in Phase II clinical trials in patients with advanced melanoma A two-phase, 2-treatment phase II trial was conducted to determine CP-675,206 We evaluated the optimal dosing regimen for central clinical trials.

  Patients who met the selection criteria suffered measurable melanoma (stage IIIc or stage IV) that was worsening or worsened after previous treatment and ECOG PS ≦ 1. In the first phase, 18 patients per treatment group were randomized to 10 mg / kg once a month (10Q1M) or 15 mg / kg every 3 months (15Q3M). If 3 or more patients in either treatment group had a complete response (CR) or partial response (PR), an additional 25 patients were included in that treatment group. The primary endpoint was tumor response (OR), and secondary endpoints were safety and survival.

  89 patients received at least one dose (44 for 10Q1M, 45 for 15Q3M), and both study groups moved to the second stage. 96% of patients suffered from stage IV disease and 57% had elevated LDH. There were no significant differences between study groups in age, gender, stage, or baseline LDH levels. Administration of median 3 times (range, 1-26 times) at 10Q1M and once (range, 1-9 times) at 15Q3M was performed with 100% compliance. Delayed administration occurred in 30% of patients treated with 10Q1M and 16% of patients treated with 15Q3M. Two patients at 10Q1M and 5 patients at 15Q3M continued the study for over 12 months.

  6 patients discontinued at 10Q1M due to the following toxicities: 3 due to diarrhea / colitis (1 patient required colectomy); 1 due to eye disorders of Grebbs disease; 1 due to pancreatitis 1 person is due to hypersensitivity reaction. Two patients were discontinued with 15Q3M: one with colitis and pancreatitis and the other with diarrhea (P = 0.14). There were no deaths due to toxicity. Administration of 15Q3M was associated with a low incidence of third or fourth degree adverse events (AEs), ie 31% compared to 41% with 10Q1M; P = 0.42.

  Responses as assessed by the investigator were CR1 and PR3 in 10Q1M, CR1 and PR2 in 15Q3M, including skin, lymph node (LN), bone, liver, lung, and adrenal responses . Only one PR patient at 10Q1M relapsed, but the remaining patient response continued (18 + -28 + months). Median survival was 10.3 months for 10Q1M and 11.0 months for 15Q3M (P = NS).

  15 mg / kg every 3 months (15Q3M) regimen for further clinical trials based on comparable antitumor effects and a trend of higher feasibility and safety compared to 10 mg / kg per month (10Q1M) Selected.

Increased antiviral titer in combination with rhesus monkey immunization Combination therapy including administration of vaccines and anti-CTLA4 antibody resulted in an increased antiviral immune response.

  FLUZONE Subvirion 1998-99 (NDC49281-362-11 influenza virus vaccine, trivalent A and B types; Aventis Pasteur Inc. (including immunized by monkeys immunized with Connaught Labs., Pasteur Merieux and Pasteur Merieux Connaught)) . The 1998-99 vaccine is available in three strains: A / Beijing / 262/95 (H1N1), A / Sydney / 5/97 (H3N2), and B / Harbin / 07/94 (B / Beijing / 184 / 93-like strains) derived from hemagglutinin A (HA). On day 0 (week 0), monkeys were immunized intramuscularly (IM) with FLUZONE and immunized again 4 weeks later (week 4). Antibody was administered according to the following schedule: Group 1 received anti-CTLA4 antibody CP-642,570 (5 mg / kg) intravenously (IV) at week 0; Group 2 was irrelevant at week 0 Control antibody (anti-KLH antibody; 5 mg / kg, IV) was administered; group 3 was IM immunized with FLUZONE at 0 weeks, and IM immunized again with FLUZONE at 4 weeks. Anti-CTLA4 antibody (5 mg / kg, IV) was administered to the eyes; group 4 was IM immunized with FLUZONE at 0 weeks, IM immunized again with FLUZONE at 4 weeks, and 4 weeks An irrelevant control antibody (anti-KLH antibody, 5 mg / kg, IV) was administered; group 5 was IM immunized with FLUSONE at 0 weeks and IM again with FLUSONE at 4 weeks, No antibody was administered. The animals were followed for 8 weeks after the first immunization with FLUZONE.

  The administered anti-CTLA4 antibody was human anti-human CTLA4 designated CP-642,570 (also referred to herein as antibody 4.1.1).

  Serum was collected 1 hour and 24 hours after administration of anti-CTLA4 and every 2 weeks thereafter. The following parameters were evaluated: anti-CTLA4 serum levels, IgG titers against FLUZONE, neopterin levels, and 2-5 adenylate synthase levels.

  Exposure was confirmed from the plasma levels of anti-CTLA4 antibody, ie plasma levels were about 75 μg / ml in 1 hour and 40-50 μg / ml in 24 hours, and were largely undetectable by 2 weeks (FIG. 4). ). No antibody level could be detected in one animal in Group 3, possibly due to injection failure or tube replacement.

  Animals were evaluated for various markers of immune activation. Neopterin levels were indefinite (Figure 5). That is, the first rapid increase in value was detected in the anti-CTLA4 group 2 weeks after immunization and treatment. 4 weeks after immunization, the level dropped to the basal level, and there was no difference between the groups including the third group and the fourth group.

  Whole blood was obtained, cell pellets were collected and assayed for 2-5 adenylate synthase. The first group and the second group were compared (FIG. 6). The data suggests that there was a detectable increase in the anti-CTLA4 group (Group 1) compared to the control group.

  In animals treated with anti-CTLA4 during the second immunization, elevated anti-FLUZONE IgG levels were detected at 6 weeks (Group 3) (FIG. 7). No effect on anti-FLUZONE titer was observed in any other group of animals. Prebleed (-1 week) (+), 0 week (white triangles), 2 weeks (black triangles), 4 weeks (white squares), 6 weeks (shaded circles), and 8 weeks ( The anti-FLUZONE IgG titer of each individual animal is shown in FIG. Data points are grouped according to the test group, ie, groups 1, 2, 3, 4, and 5. The value shown in the box indicates the repeated titer of the same sample.

  FIG. 9 shows anti-FLUZONE serum IgG titers at 6 weeks in rhesus monkeys. Individual animal results were grouped according to test group, from which group 3 animals (administered with anti-CTLA4 antibody at 4 weeks) had anti-FLUZONE IgG (flu-IgG) compared to other animals. This suggests an increase in titer. One animal showed an increase in flu-IgG titer, but no anti-CTLA4 exposure (by plasma level assay) could be confirmed. Some rapid increase in anti-flu antibody titer was observed in the control group, but the titer was small in magnitude.

  In summary, an increase in flu-IgG and 2-5 adenylate synthase was observed in animals administered anti-CTLA4 antibody, indicating that anti-CTLA4 antibody administered to virus-infected patients is It is suggested to enhance therapeutic benefit for immunized patients and / or when used in combination with antiviral therapy.

  The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety.

  While the invention has been disclosed with reference to particular embodiments, other embodiments and modifications of the invention can be devised by other persons skilled in the art without departing from the true spirit and scope of the invention. Is clear. The appended claims are to be construed to include all such embodiments and equivalent variations.

FIG. 1 includes FIGS. 1A-1D, which show the nucleotide and amino acid sequences of anti-CTLA4 antibody 4.1.1. FIG. 1A shows the full length nucleotide sequence (SEQ ID NO: 1) of the 4.1.1 heavy chain. FIG. 1B shows the 4.1.1 heavy chain full-length amino acid sequence (SEQ ID NO: 2) and the 4.1.1 heavy chain variable region amino acid sequence shown between brackets “[]” (SEQ ID NO: 3). Indicates. The amino acid sequence of each 4.1.1 heavy chain CDR is underlined. The CDR sequences are as follows: CDR1: GFTFSHGHMH (SEQ ID NO: 4); CDR2: VIWYDGRNKYYADSV (SEQ ID NO: 5); and CDR3: GGHGFPFDY (SEQ ID NO: 6). FIG. 1C shows the nucleotide sequence of the 4.1.1 light chain (SEQ ID NO: 7). FIG. 1D shows the amino acid sequence of the full length 4.1.1 light chain (SEQ ID NO: 8) and the variable region shown between brackets “[]” (SEQ ID NO: 9). The amino acid sequence of each CDR is shown as follows: CDR1: RASQSISSSFLA (SEQ ID NO: 10); CDR2: GASSRAT (SEQ ID NO: 11); and CDR3: QQYGTSPWT (SEQ ID NO: 12). FIG. 2 includes the FIGS. 2A-2D, showing the nucleotide and amino acid sequences of anti-CTLA4 antibody 4.13.1. FIG. 2A shows the 4.13.1 heavy chain full length nucleotide sequence (SEQ ID NO: 13). FIG. 2B shows the 4.13.1 heavy chain full-length amino acid sequence (SEQ ID NO: 14) and the 4.13.1 heavy chain variable region amino acid sequence shown between brackets “[]” (SEQ ID NO: 15). Indicates. The amino acid sequence of each 4.13.1 heavy chain CDR is underlined. The CDR sequences are as follows: CDR1: GFTSSHGIH (SEQ ID NO: 16); CDR2: VIWYDGRNKDYADSV (SEQ ID NO: 12); and CDR3: VAPLGPLDY (SEQ ID NO: 18). FIG. 2C shows the nucleotide sequence of the 4.13.1 light chain (SEQ ID NO: 19). FIG. 2D shows the amino acid sequence of the full-length 4.13.1 light chain (SEQ ID NO: 20) and the variable region shown between brackets “[]” (SEQ ID NO: 21). The amino acid sequence of each CDR is shown as follows: CDR1: RASQSVSSYLA (SEQ ID NO: 22); CDR2: GASSSRAT (SEQ ID NO: 23); and CDR3: QQYGRSPFT (SEQ ID NO: 24). FIG. 3 includes FIGS. 3A-3D showing the nucleotide and amino acid sequences of anti-CTLA4 antibody CP-675,206. FIG. 3A shows the full length nucleotide sequence of CP-675,206 heavy chain (SEQ ID NO: 25). FIG. 3B shows the full length amino acid sequence of CP-675,206 heavy chain (SEQ ID NO: 26) and the amino acid sequence of the CP-675,206 heavy chain variable region shown between brackets “[]” (SEQ ID NO: 27). Indicates. The amino acid sequence of each CP-675,206 heavy chain CDR is underlined. The CDR sequences are as follows: CDR1: GTFFSSYGMH (SEQ ID NO: 28); CDR2: VIWYDGSNKYYADSV (SEQ ID NO: 29); and CDR3: DPRGATYLYYYYGMMDV (SEQ ID NO: 30). FIG. 3C shows the nucleotide sequence of CP-675,206 light chain (SEQ ID NO: 31). FIG. 3D shows the amino acid sequence of full-length CP-675,206 light chain (SEQ ID NO: 32) and the variable region shown between brackets “[]” (SEQ ID NO: 33). The amino acid sequence of each CDR is shown as follows: CDR1: RASQSINSYLD (SEQ ID NO: 34); CDR2: AASSLQS (SEQ ID NO: 35); and CDR3: QQYYSTPFT (SEQ ID NO: 36). FIG. 5 is a graph showing plasma serum levels of rhesus monkeys after exposure to anti-CTLA4 antibody. All rhesus monkeys received intramuscular (IM) administration of influenza vaccine FLUZONE again at week 0 and week 4. In addition to FLUZONE, animals in group 1 (animal numbers 1 (black circles), 2 (black squares), and 3 (black triangles)) received 5 mg / kg at 0 weeks, intravenous (IV) anti-CTLA4 antibody Received a single dose of 4.1.1 (also referred to as CP-642,570). Group 3 animals (animal numbers 4 (open circles), 5 (open squares), 6 (open triangles), and 7 (marked with “x”)) were 5 mg / kg at week 0, IV unrelated humans A single dose of antibody (anti-KLH antibody) was received. Of neopterin, a marker implicating immune activity, in rhesus monkeys IM immunized with FLUSONE at 0 and 4 weeks and administered 5 mg / kg IV at 4 weeks with anti-CTLA4 antibody 4.1.1 It is a figure which shows a serum level. Animal number AG40 (black diamonds), number AK80 (black squares) and number AM90 (black triangles) are group 1 and were given anti-CTLA4 antibody and FLUZONE on day 0 and then FLUZONE on week 0. Animal number AK76 (x), number AM84 (*), and number BC13 (open circles) are the second group of controls, to which FLUZONE was administered at weeks 0 and 4 and 5 mg at week 0 of the protocol. / Kg, IV irrelevant human antibody (anti-KLH antibody) was also administered. 2- in a leukocyte pellet isolated from rhesus monkey blood IM immunized with FLUZONE at 0 and 4 weeks and further dosed with anti-CTLA4 antibody 4.1.1 (5 mg / kg, IV) at 0 weeks It is a graph which shows the level of 5 adenylate synthase. Group 1 (FLUZONE IM at weeks 0 and 4 and anti-CTLA4 antibody at week 0) and Group 2 (FLUZONE IM at weeks 0 and 4) and an irrelevant antibody (anti-KLH, 5 mg at week 0, respectively) / Kg, IV) from each animal) at 2 weeks (light gray shaded bars), 4 weeks (dark gray shaded bars) and 6 weeks (non-shaded bars) Peripheral blood cells were obtained. If the value exceeds 4000 pmol / dl, the value is shown in each bar. Cells were pelleted and the level of 2-5 adenylate synthase in the pellet obtained from each animal was evaluated. It is a graph which shows IgG anti- FLUZONE titer in the rhesus monkey which administered the anti- CTLA4 antibody. Group 1 (open triangle; administered FLUZONE at 0 and 4 weeks, administered anti-CTLA4 antibody at 0 week), Group 2 (open square; administered FLUZONE at 0 and 4 weeks, unrelated to 0 week Human anti-KLH antibody), Group 3 (filled circles; administered FLUZONE at 0 and 4 weeks), Group 4 (open circles; administered FLUZONE at 0 and 4 weeks) Serum anti-FLUZONE IgG titers for animals in administration (administered irrelevant human anti-KLH antibody at 4 weeks) and Group 5 (black triangle; administered FLUZONE but not antibody at 0 and 4 weeks) Was evaluated. FLUZONE was administered IM, and the antibody was administered IV at 5 mg / kg. Anti-FLUZONE IgG titers one week prior to immunization with FLUZONE (week 1, also referred to as “prebleed”), then at weeks 0, 2, 4, 6 and 8 Was evaluated. Animals in Group 3 (immunized with FLUZONE at 0 and 4 weeks and administered anti-CTLA4 antibody at 4 weeks) showed increased anti-FLUZONE IgG serum titers compared to animals in other groups . Rhesus monkeys immunized with FLUZONE at 0 and 4 weeks, administered anti-CTLA4 antibody at 0 weeks (group 1), immunized with FLUZONE at 0 and 4 weeks, unrelated antibodies at 0 weeks Rhesus monkeys (Group 2), immunized with FLUZONE at 0 and 4 weeks, and rhesus monkeys (Group 3) administered anti-CTLA4 antibody at 4 weeks, immunized with FLUZONE at 0 and 4 weeks Graph showing anti-FLUZONE IgG serum titers in rhesus monkeys (group 4) that were made and administered irrelevant antibodies at week 0 and rhesus monkeys immunized with FLUZONE at weeks 0 and 4 (group 5) is there. Data points are separated by group of animals, and the titer of each individual animal is determined by the following data points: prebleed (-1 week; +), week 0 (white triangles), week 2 (black) (Triangle) Within week 4 (white squares), 6 weeks (black circles), and 8 weeks (white circles). 6 is a bar graph showing anti-FLUZONE IgG antibody titers at 6 weeks in rhesus monkeys (Groups 1-5) immunized with FLUZONE at 0 and 4 weeks. Group 1 animals received anti-CTLA4 administration (5 mg / kg, IV) at week 0. Group 2 animals received anti-KLH, an irrelevant antibody (5 mg / kg, IV) at week 0. Group 3 animals received anti-CTLA4 administration (5 mg / kg, IV) at 4 weeks. Group 4 animals received anti-KLH, an irrelevant antibody (5 mg / kg, IV) at 4 weeks. Group 5 animals received only immunization with FLUZONE at 0 and 4 weeks.

Claims (20)

A method of treating cancer in a patient in need of cancer treatment, wherein a therapeutically effective amount of CP-675,206 anti-CTLA4 antibody is administered to said patient in combination with a therapeutically effective amount of at least one therapeutic agent. Administering the cancer, wherein the cancer and the agent are
(A) when the cancer is non-Hodgkin lymphoma (NHL) and the agent is rituximab;
(B) when the cancer is NHL and the agent is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP);
(C) when the cancer is NHL and the agent is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R);
(D) when the cancer is lung cancer and the agent is bevacizumab;
(E) the cancer is non-small cell lung cancer (NSCLC) and the agent is gefitinib;
(F) the cancer is NSCLC and the agent is bevacizumab;
(G) the cancer is NSCLC, the agent is a taxane and gemcitabine, and the taxane is selected from the group consisting of docetaxel and paclitaxel;
(H) when the cancer is NSCLC and the agent is a taxane and a platinum compound;
(I) when the cancer is NSCLC and the agent is docetaxel;
(J) when the cancer is NSCLC and the agent is erlotinib;
(K) when the cancer is NSCLC and the agent is pemetrexed;
(L) When the cancer is NSCLC and the agent is a platinum compound;
(M) the cancer is gastric cancer and the agent is irinotecan;
(N) the cancer is gastric cancer and the agent is fluorouracil and leucovorin;
(O) the cancer is liver cancer and the agents are doxorubicin, ifosfamide and vincristine;
(P) the cancer is liver cancer and the agents are doxorubicin and vincristine;
(Q) the cancer is colorectal cancer (CRC) and the agent is fluorouracil;
(R) the cancer is CRC and the agent is capecitabine;
(S) when the cancer is CRC and the agents are fluorouracil, leucovorin and oxaliplatin (FOLFOX);
(T) when the cancer is CRC and the agents are fluorouracil, leucovorin and irinotecan (FOLFIRI);
(U) the cancer is CRC and the agent is cetuximab;
(V) the cancer is chronic myelogenous leukemia (CML) and the agent is imatinib mesylate;
(W) the cancer is chronic lymphocytic leukemia (CLL) and the agent is imatinib mesylate;
(X) the cancer is pancreatic cancer and the agent is gemcitabine;
(Y) when the cancer is breast cancer and the agent is a taxane;
(Z) when the cancer is breast cancer and the agent is cyclophosphamide, doxorubicin and taxane;
(Aa) the cancer is breast cancer and the agent is selected from the group consisting of tamoxifen, anastrazol, letrozole, and fulvestrant;
(Bb) when the cancer is breast cancer and the agent is trastuzumab;
(Cc) when the cancer is breast cancer and the agent is bevacizumab;
(Dd) when the cancer is breast cancer and the agent is cetuximab;
(Ee) when the cancer is breast cancer and the agent is axitinib;
(Ff) when the cancer is bladder cancer and the agent is Calmette Guerin (BCG);
(Gg) when the cancer is bladder cancer and the agents are gemcitabine and cisplatin;
(Hh) when the cancer is melanoma and the agent is interferon alpha;
(Ii) the cancer is multiple myeloma and the agent is bortezomib;
(Jj) when the cancer is multiple myeloma and the agent is dexamethasone and thalidomide;
And (kk) A method selected from the group consisting of: the cancer is ovarian cancer and the agent is carboplatin and paclitaxel.   The method of claim 1, wherein the treatment is selected from the group consisting of neoadjuvant therapy, adjuvant therapy, first line therapy, second line therapy, and third line therapy.   2. The method of claim 1, wherein the agent is administered sequentially with or concurrently with the antibody.   The method according to subparagraph (i) of claim 1, wherein the taxane is paclitaxel and the platinum compound is carboplatin.   5. The method of claim 4, further comprising administering at least one agent selected from the group consisting of bevacizumab, PF03512676, and sunitinib.   2. The method of claim 1 (i), further comprising administering at least one agent selected from the group consisting of erlotinib and pemetrexed, wherein the treatment comprises a second line therapy.   The method of claim 1, wherein the therapeutically effective amount of the antibody, or portion thereof, is about 1 mg / kg to 40 mg / kg.   8. The method of claim 7, wherein the amount is from about 3 mg / kg to 15 mg / kg.   The method of claim 1, subparagraph (s), wherein said treatment is selected from the group consisting of first line therapy and adjuvant therapy after surgical resection of primary colon tumor.   The subparagraph (x) of claim 1, wherein the pancreatic cancer is selected from the group consisting of unresectable stage II, locally advanced stage III, and metastatic stage IV, wherein the treatment comprises first line therapy The method described.   2. The method of subparagraph (x) of claim 1, wherein the antibody is administered after the final administration of gemcitabine.   12. The method of claim 11, wherein the antibody is administered at least about 3 weeks and within at least 6 weeks after the last dose of gemcitabine.   The method of claim 1, subparagraph (y), wherein said treatment comprises first line therapy.   The method of claim 1, subparagraph (kk), wherein said treatment comprises first line therapy.   The sub-paragraph (l) of claim 1, wherein the NSCLC responds or remains stable after approximately 6 doses of the platinum compound and further administers the antibody after performing the platinum-based therapy. The method described.   A method for preventing or treating HIV infection or preventing, treating or delaying the onset of AIDS in a patient in need thereof, wherein a therapeutically effective amount of anti-CTLA4 antibody CP-675,206 is administered to said patient An HIV protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, a nucleoside / nucleotide reverse transcriptase inhibitor, a CCR5 antagonist, an inhibitor of the interaction of CD4 and gp120, an HIV fusion inhibitor, an HIV integrase Administering a therapeutically effective amount of at least one antiviral agent selected from the group consisting of an inhibitor, an RNase H inhibitor, a prenylation inhibitor, and a maturation inhibitor.   17. The method of claim 16, wherein the CCR5 antagonist is maraviroc.   18. The method of claim 17, further comprising assessing the HIV co-receptor tropism.   A method for preventing or treating HIV infection or preventing, treating or delaying the onset of AIDS in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of anti-CTLA4 antibody and maraviroc A method comprising steps. 20. The method of claim 19, wherein the anti-CTLA4 antibody is selected from the group consisting of CP-675,206 and ipilimumab.

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