# US 2008/0305104 A1 · Cytotoxicity mediation of cells evidencing surface expression of TROP-2 > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2008/0305104 A1 - Document ID: US20080305104A1 - Status: Published application - Kind: A1 - Application number: 12/082,647 - Filed: 2008-04-11 - Published: 2008-12-11 - Earliest claimed: 2006-02-24 - Inventors: David S. F. Young; Helen P. Findlay; Susan E. Hahn; Luis A.G. DaCruz; Alison L. Ferry - Web page: https://patentgrep.com/patent/US20080305104A1 ## CPC - C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere} - A61P 35/00: Antineoplastic agents - C07K 16/30: from tumour cells - G01N 33/57557: {of other specific parts of the body, e.g. brain} - G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites} - G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells} - A61K 2039/505: {comprising antibodies} - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues - C07K 2317/734: Complement-dependent cytotoxicity [CDC] - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract This invention relates to the staging, diagnosis and treatment of cancerous diseases (both primary tumors and tumor metastases), particularly to the mediation of cytotoxicity of tumor cells; and most particularly to the use of cancerous disease modifying antibodies (CDMAB), optionally in combination with one or more CDMAB/chemotherapeutic agents, as a means for initiating the cytotoxic response. The invention further relates to binding assays, which utilize the CDMAB of the instant invention. The anti-cancer antibodies can be conjugated to toxins, enzymes, radioactive compounds, cytokines, interferons, target or reporter moieties and hematogenous cells. ## Claims ### Claim 1 A method of reduction of a human pancreatic, breast, prostate, ovarian or colon tumor in a mammal, wherein said human pancreatic, breast, prostate, ovarian or colon tumor expresses at least one epitope of an antigen which specifically binds to the isolated monoclonal antibody produced by the hybridoma cell line deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, which CDMAB is characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target antigen, comprising administering to said mammal said monoclonal antibody or CDMAB thereof in an amount effective to result in a reduction of said mammal's pancreatic, breast, prostate, ovarian or colon tumor burden. ### Claim 2 (depends on 1) The method of claim 1 wherein said isolated monoclonal antibody is conjugated to a cytotoxic moiety. ### Claim 3 (depends on 2) The method of claim 2 wherein said cytotoxic moiety is a radioactive isotope. ### Claim 4 (depends on 1) The method of claim 1 wherein said isolated monoclonal antibody or CDMAB thereof activates complement. ### Claim 5 (depends on 1) The method of claim 1 wherein said isolated monoclonal antibody or CDMAB thereof mediates antibody dependent cellular cytotoxicity. ### Claim 6 (depends on 1) The method of claim 1 wherein said isolated monoclonal antibody is a humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or an antigen binding fragment produced from said humanized antibody. ### Claim 7 (depends on 1) The method of claim 1 wherein said isolated monoclonal antibody is a chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or an antigen binding fragment produced from said chimeric antibody. ### Claim 8 A method of reduction of a human pancreatic, breast, prostate, ovarian or colon tumor susceptible to antibody induced cellular cytotoxicity in a mammal, wherein said human pancreatic, breast, prostate, ovarian or colon tumor expresses at least one epitope of an antigen which specifically binds to the isolated monoclonal antibody produced by the hybridoma cell line deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, which CDMAB is characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target antigen, comprising administering to said mammal said monoclonal antibody or said CDMAB thereof in an amount effective to result in a reduction of said mammal's pancreatic, breast, prostate, ovarian or colon tumor burden. ### Claim 9 (depends on 8) The method of claim 8 wherein said isolated monoclonal antibody is conjugated to a cytotoxic moiety. ### Claim 10 (depends on 9) The method of claim 9 wherein said cytotoxic moiety is a radioactive isotope. ### Claim 11 (depends on 8) The method of claim 8 wherein said isolated monoclonal antibody or CDMAB thereof activates complement. ### Claim 12 (depends on 8) The method of claim 8 wherein said isolated monoclonal antibody or CDMAB thereof mediates antibody dependent cellular cytotoxicity. ### Claim 13 (depends on 8) The method of claim 8 wherein said isolated monoclonal antibody is a humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or an antigen binding fragment produced from said humanized antibody. ### Claim 14 (depends on 8) The method of claim 8 wherein said isolated monoclonal antibody is a chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or an antigen binding fragment produced from said chimeric antibody. ### Claim 15 A method of reduction of a human pancreatic, breast, prostate, ovarian or colon tumor in a mammal, wherein said human pancreatic, breast, prostate, ovarian or colon tumor expresses at least one epitope of an antigen which specifically binds to the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, which CDMAB is characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target antigen, comprising administering to said mammal said monoclonal antibody or CDMAB thereof in conjunction with at least one chemotherapeutic agent in an amount effective to result in a reduction of said mammal's pancreatic, breast, prostate, ovarian or colon tumor burden. ### Claim 16 (depends on 15) The method of claim 15 wherein said isolated monoclonal antibody is conjugated to a cytotoxic moiety. ### Claim 17 (depends on 16) The method of claim 16 wherein said cytotoxic moiety is a radioactive isotope. ### Claim 18 (depends on 15) The method of claim 15 wherein said isolated monoclonal antibody or CDMAB thereof activates complement. ### Claim 19 (depends on 15) The method of claim 15 wherein said isolated monoclonal antibody or CDMAB thereof mediates antibody dependent cellular cytotoxicity. ### Claim 20 (depends on 15) The method of claim 15 wherein said isolated monoclonal antibody is a humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or an antigen binding fragment produced from said humanized antibody. ### Claim 21 (depends on 15) The method of claim 15 wherein said isolated monoclonal antibody is a chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or an antigen binding fragment produced from said chimeric antibody. ### Claim 22 Use of monoclonal antibodies for reduction of human breast, pancreatic, ovarian, prostate or colon tumor burden, wherein said human breast, pancreatic, ovarian, prostate or colon tumor expresses at least one epitope of an antigen which specifically binds to the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, which CDMAB is characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target antigen, comprising administering to said mammal said monoclonal antibody or CDMAB thereof in an amount effective to result in a reduction of said mammal's human breast, pancreatic, ovarian, prostate or colon tumor burden. ### Claim 23 (depends on 22) The method of claim 22 wherein said isolated monoclonal antibody is conjugated to a cytotoxic moiety. ### Claim 24 (depends on 23) The method of claim 23 wherein said cytotoxic moiety is a radioactive isotope. ### Claim 25 (depends on 22) The method of claim 22 wherein said isolated monoclonal antibody or CDMAB thereof activates complement. ### Claim 26 (depends on 22) The method of claim 22 wherein said isolated monoclonal antibody or CDMAB thereof mediates antibody dependent cellular cytotoxicity. ### Claim 27 (depends on 22) The method of claim 22 wherein said isolated monoclonal antibody is a humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05. ### Claim 28 (depends on 22) The method of claim 22 wherein said isolated monoclonal antibody is a chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05. ### Claim 29 Use of monoclonal antibodies for reduction of human breast, pancreatic, ovarian, prostate or colon tumor burden, wherein said human breast, pancreatic, ovarian, prostate or colon tumor expresses at least one epitope of an antigen which specifically binds to the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, which CDMAB is characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target antigen, comprising administering to said mammal said monoclonal antibody or CDMAB thereof; in conjunction with at least one chemotherapeutic agent in an amount effective to result in a reduction of said mammal's human breast, pancreatic, ovarian, prostate or colon tumor burden. ### Claim 30 (depends on 29) The method of claim 29 wherein said isolated monoclonal antibody is conjugated to a cytotoxic moiety. ### Claim 31 (depends on 30) The method of claim 30 wherein said cytotoxic moiety is a radioactive isotope. ### Claim 32 (depends on 29) The method of claim 29 wherein said isolated monoclonal antibody or CDMAB thereof activates complement. ### Claim 33 (depends on 29) The method of claim 29 wherein said isolated monoclonal antibody or CDMAB thereof mediates antibody dependent cellular cytotoxicity. ### Claim 34 (depends on 29) The method of claim 29 wherein said isolated monoclonal antibody is a humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05. ### Claim 35 (depends on 29) The method of claim 29 wherein said isolated monoclonal antibody is a chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05. ### Claim 36 A process for reduction of a human breast, pancreatic, ovarian, prostate or colon tumor which expresses at least one epitope of human TROP-2 antigen which is specifically bound by the isolated monoclonal antibody produced by hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, comprising: administering to an individual suffering from said human tumor, at least one isolated monoclonal antibody or CDMAB thereof that binds the same epitope or epitopes as those bound by the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05; wherein binding of said epitope or epitopes results in a reduction of breast, pancreatic, ovarian, prostate or colon tumor burden. ### Claim 37 A process for reduction of a human breast, pancreatic, ovarian, prostate or colon tumor which expresses at least one epitope of human TROP-2 antigen which is specifically bound by the isolated monoclonal antibody produced by hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, comprising: administering to an individual suffering from said human tumor, at least one isolated monoclonal antibody or CDMAB thereof, that binds the same epitope or epitopes as those bound by the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05; in conjunction with at least one chemotherapeutic agent; wherein said administration results in a reduction of tumor burden. ### Claim 38 A binding assay to determine a presence of cancerous cells in a tissue sample selected from a human tumor, which is specifically bound by the isolated monoclonal antibody produced by hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, the humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or the chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05, comprising: providing a tissue sample from said human tumor; providing at least one of said isolated monoclonal antibody, said humanized antibody, said chimeric antibody or CDMAB thereof that recognizes the same epitope or epitopes as those recognized by the isolated monoclonal antibody produced by a hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05; contacting at least one said provided antibodies or CDMAB thereof with said tissue sample; and determining binding of said at least one provided antibody or CDMAB thereof with said tissue sample; whereby the presence of said cancerous cells in said tissue sample is indicated. ### Claim 39 A binding assay to determine the presence of cells which express TROP-2 which is specifically recognized by the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, the humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or the chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05, comprising: providing a cell sample; providing the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, said humanized antibody, said chimeric antibody or CDMAB thereof; contacting said isolated monoclonal antibody or said antigen binding fragment with said cell sample; and determining binding of said isolated monoclonal antibody or CDMAB thereof with said cell sample; whereby the presence of cells which express an antigen of TROP-2 which is specifically bound by said isolated monoclonal antibody or said CDMBA thereof is determined. ### Claim 40 A method for inducing complement dependent cytotoxicity of cancerous cells, which express at least one epitope of TROP-2 on the cell's surface, which at least one epitope, when bound by the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as 141205-05 or an antigen binding fragment produced from said isolated monoclonal antibody results in cell cytotoxicity, comprising: providing the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as 141205-05 or an antigen binding fragment produced from said isolated monoclonal antibody, and contacting said cancerous cells with said isolated monoclonal antibody or said antigen binding fragment; whereby cytotoxicity occurs as a result of binding of said isolated monoclonal antibody or said antigen binding fragment with said at least one epitope of TROP-2. ### Claim 41 (depends on 40) The method of claim 40 wherein said isolated monoclonal antibody is conjugated to a cytotoxic moiety. ### Claim 42 (depends on 41) The method of claim 41 wherein said cytotoxic moiety is a radioactive isotope. ### Claim 43 (depends on 40) The method of claim 40 wherein said isolated monoclonal antibody activates complement. ### Claim 44 (depends on 40) The method of claim 40 wherein said isolated monoclonal antibody mediates cellular cytotoxicity. ### Claim 45 (depends on 40) The method of claim 40 wherein said monoclonal antibody is a humanized antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as 141205-05 or an antigen binding fragment produced from said humanized antibody. ### Claim 46 (depends on 40) The method of claim 40 wherein said monoclonal antibody is a chimeric antibody of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as 141205-05 or an antigen binding fragment produced from said chimeric antibody. ### Claim 47 A method for inducing complement dependent cytotoxicity of cancerous cells, which express at least one epitope of TROP-2 on the cell's surface, which at least one epitope, when bound by the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as 141205-05 or an antigen binding fragment produced from said isolated monoclonal antibody results in cell cytotoxicity, comprising: providing an isolated monoclonal antibody which competitively inhibits binding of the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as 141205-05 or of an antigen binding fragment produced from said isolated monoclonal antibody, and which when bound by said at least one epitope of TROP-2, results in cell cytotoxicity; and contacting said cancerous cells with said isolated monoclonal antibody or said antigen binding fragment; whereby cytotoxicity occurs as a result of binding of said isolated monoclonal antibody or said antigen binding fragment with said at least one epitope of TROP-2. ### Claim 48 A monoclonal antibody which specifically binds to the same epitope or epitopes as the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05. ### Claim 49 An isolated monoclonal antibody or CDMAB thereof, which specifically binds to human TROP-2, in which the isolated monoclonal antibody or CDMAB thereof reacts with the same epitope or epitopes of human TROP-2 as the isolated monoclonal antibody produced by a hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05; said isolated monoclonal antibody or CDMAB thereof being characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target human TROP-2 antigen. ### Claim 50 An isolated monoclonal antibody or CDMAB thereof that recognizes the same epitope or epitopes as those recognized by the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05; said monoclonal antibody or CDMAB thereof being characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target epitope or epitopes. ### Claim 51 A humanized antibody that specifically binds the same epitope or epitopes of human TROP-2 as the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, comprising: a heavy chain variable region comprising the complementarity determining region amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; and a light chain variable region comprising the complementarity determining region amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; or a human TROP-2 binding fragment thereof. ### Claim 52 A humanized antibody that specifically binds the same epitope or epitopes of human TROP-2 as the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 having IDAC Accession No. 141205-05, comprising: a heavy chain variable region comprising the complementarity determining region amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; and a light chain variable region comprising the complementarity determining region amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; and variable domain framework regions from the heavy and light chains of a human antibody or human antibody consensus framework; or a human TROP-2 binding fragment thereof. ### Claim 53 A humanized antibody that specifically binds human TROP-2, wherein said monoclonal antibody comprises a heavy chain variable region amino acid sequence of SEQ ID NO:7; and a light chain variable region amino acid sequence selected of SEQ ID NO:8; or a human TROP-2 binding fragment thereof. ### Claim 54 A humanized antibody that specifically binds human TROP-2, wherein said monoclonal antibody comprises a heavy chain variable region amino acid sequence of SEQ ID NO:7; and a light chain variable region amino acid sequence selected of SEQ ID NO:9; or a human TROP-2 binding fragment thereof. ### Claim 55 A humanized antibody that specifically binds human TROP-2, wherein said monoclonal antibody comprises a heavy chain variable region amino acid sequence of SEQ ID NO:10; and a light chain variable region amino acid sequence selected of SEQ ID NO:8; or a human TROP-2 binding fragment thereof. ### Claim 56 A humanized antibody that specifically binds human TROP-2, wherein said monoclonal antibody comprises a heavy chain variable region amino acid sequence of SEQ ID NO:10; and a light chain variable region amino acid sequence selected of SEQ ID NO:9; or a human TROP-2 binding fragment thereof. ### Claim 57 (depends on 1, 2, 3, 6, 7, 8, 17, 49, 50, 54, 55) A composition effective for treating a human pancreatic, prostate, ovarian, breast or colon tumor comprising in combination: an antibody or CDMAB of any one of claims 1, 2, 3, 6, 7, 8, 17, 49, 50, 54, 55, or 56; a conjugate of said antibody or an antigen binding fragment thereof with a member selected from the group consisting of cytotoxic moieties, enzymes, radioactive compounds, cytokines, interferons, target or reporter moieties and hematogenous cells; and a requisite amount of a pharmacologically acceptable carrier; wherein said composition is effective for treating said human pancreatic, breast, prostate, ovarian or colon tumor. ### Claim 58 (depends on 1, 2, 3, 6, 7, 8, 17, 49, 50, 54, 55) A composition effective for treating a human pancreatic, breast, prostate, ovarian or colon tumor comprising in combination: an antibody or CDMAB of any one of claims 1, 2, 3, 6, 7, 8, 17, 49, 50, 54, 55, or 56; and a requisite amount of a pharmacologically acceptable carrier; wherein said composition is effective for treating said human pancreatic, breast, prostate, ovarian or colon tumor. ### Claim 59 (depends on 1, 2, 3, 6, 7, 8, 17, 49, 50, 54, 55) A composition effective for treating a human pancreatic, breast, prostate, ovarian or colon tumor comprising in combination: a conjugate of an antibody, antigen binding fragment, or CDMAB of any one of claims 1, 2, 3, 6, 7, 8, 17, 49, 50, 54, 55, or 56; with a member selected from the group consisting of cytotoxic moieties, enzymes, radioactive compounds, cytokines, interferons, target or reporter moieties and hematogenous cells; and a requisite amount of a pharmacologically acceptable carrier; wherein said composition is effective for treating said human pancreatic, breast, prostate, ovarian or colon tumor. ### Claim 60 An assay kit for detecting the presence of a human cancerous tumor, wherein said human cancerous tumor expresses at least one epitope of an antigen which specifically binds to the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, which CDMAB is characterized by an ability to competitively inhibit binding of said isolated monoclonal antibody to its target antigen, the kit comprising the isolated monoclonal antibody produced by the hybridoma deposited with the IDAC as accession number 141205-05 or a CDMAB thereof, and means for detecting whether the monoclonal antibody, or a CDMAB thereof, is bound to a polypeptide whose presence, at a particular cut-off level, is diagnostic of said presence of said human cancerous tumor.