TGF-β1 specific antibodies and methods and uses thereof
| Title: | TGF-β1 specific antibodies and methods and uses thereof |
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| Patent Number: | 10035,851 |
| Publication Date: | July 31, 2018 |
| Appl. No: | 15/341077 |
| Application Filed: | November 02, 2016 |
| Abstract: | Specific binding members, particularly antibodies and fragments thereof, which bind to transforming growth factor beta 1 (TGF-β1) are provided, particularly recognizing human and mouse TGF-β1 and not recognizing or binding TGF-β2 or TGF-β3. Particular antibodies are provided which specifically recognize and neutralize TGF-β1. These antibodies are useful in the diagnosis and treatment of conditions associated with activated or elevated TGF-β1, including cancer, and for modulating immune cells and immune response, including immune response to cancer or cancer antigens. The anti-TGF-β1 antibodies, variable regions or CDR domain sequences thereof, and fragments thereof may also be used in therapy in combination with chemotherapeutics, immune modulators, or anti-cancer agents and/or with other antibodies or fragments thereof. Antibodies of this type are exemplified by the novel antibodies hereof, including antibody 13A1, whose sequences are provided herein. |
| Inventors: | Van Snick, Jacques (Brussels, BE); Uyttenhove, Catherine (Brussels, BE); Boon, Thierry (Brussels, BE) |
| Assignees: | LUDWIG INSTITUTE FOR CANCER RESEARCH LTD. (New York, NY, US) |
| Claim: | 1. An isolated nucleic acid which comprises a sequence encoding an antibody or fragment thereof which recognizes human and mouse transforming growth factor beta 1 (TGF-β1) and does not react with TGF-β2 and does not react with TGF-β3, wherein the antibody or fragment neutralizes activity of TGF-β1, and is an antibody or fragment comprising a heavy chain variable region comprising CDR domain sequences CDR1 GYTFTNYW (SEQ ID NO: 11), CDR2 IYPGNSDT (SEQ ID NO: 12) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5) or comprising CDR domain sequences CDR1 GYTFTNYWMH (SEQ ID NO: 3), CDR2 TIYPGNSDTN (SEQ ID NO: 4) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5), and a light chain variable region comprising CDR domain sequences CDR1 ESVDNYGISF (SEQ ID NO: 6), CDR2 YAAS (SEQ ID NO: 7) and CDR3 QQSKEVPRT (SEQ ID NO: 8). |
| Claim: | 2. The nucleic acid of claim 1 which encodes an antibody or antibody fragment comprising a heavy chain variable region comprising CDR domain sequences CDR1 GYTFTNYW (SEQ ID NO: 11), CDR2 IYPGNSDT (SEQ ID NO: 12) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5) and a light chain variable region comprising CDR domain sequences CDR1 ESVDNYGISF (SEQ ID NO: 6), CDR2 YAAS (SEQ ID NO: 7) and CDR3 QQSKEVPRT (SEQ ID NO: 8). |
| Claim: | 3. The nucleic acid of claim 1 which encodes an antibody or antibody fragment comprising a heavy chain variable region comprising CDR domain sequences CDR1 GYTFTNYWMH (SEQ ID NO: 3), CDR2 TIYPGNSDTN (SEQ ID NO: 4) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5) and a light chain variable region comprising CDR domain sequences CDR1 ESVDNYGISF (SEQ ID NO: 6), CDR2 YAAS (SEQ ID NO: 7) and CDR3 QQSKEVPRT (SEQ ID NO: 8). |
| Claim: | 4. The nucleic acid of claim 1 which encodes an antibody or antibody fragment comprising a heavy chain variable region amino acid sequence selected from the amino acid sequence SEQ ID NO: 1, or variants thereof having at least 90% amino acid identity to SEQ ID NO:1. |
| Claim: | 5. The nucleic acid of claim 1 or 4 which encodes an antibody or antibody fragment comprising a light chain variable region comprising an amino acid sequence selected from the amino acid sequence as set out in SEQ ID NO: 2, or variants thereof having at least 90% amino acid identity to SEQ ID NO:2. |
| Claim: | 6. The nucleic acid of claim 1 which comprises DNA. |
| Claim: | 7. A recombinant DNA molecule comprising the sequence of claim 1 . |
| Claim: | 8. The recombinant DNA molecule of claim 7 , wherein said sequence is operatively linked to an expression control sequence. |
| Claim: | 9. A unicellular host transformed with a recombinant DNA molecule of claim 7 or 8 . |
| Claim: | 10. A vector which comprises the recombinant DNA molecule of claim 7 or 8 . |
| Claim: | 11. An isolated host vector system for the production of an antibody or fragment thereof which comprises the vector of claim 10 in a suitable host cell. |
| Claim: | 12. A method of preparing an antibody or fragment thereof which recognizes human and mouse transforming growth factor beta 1 (TGF-β1) and does not react with TGF-β2 and does not react with TGF-β3, wherein the antibody or fragment neutralizes activity of TGF-β1, which comprises expressing the nucleic add of claim 1 or any one of claims 2 - 4 under conditions to bring about expression of said antibody or fragment, and recovering the antibody or fragment. |
| Patent References Cited: | 5571714 November 1996 Dasch et al. 6492497 December 2002 Thompson et al. 2009/0202526 August 2009 Pons 2009/0285810 November 2009 Adams et al. 2010/0196359 August 2010 Kato et al. 2010/0291545 November 2010 Wakita et al. 2012/0141465 June 2012 Croft et al. 2012/0328660 December 2012 Tsuji et al. 00020581 April 2000 00066631 November 2000 05097832 October 2005 06086469 August 2006 06116002 November 2006 07076391 July 2007 |
| Other References: | Ahmadzadeh, M et al (2005) TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells J Immunol 174(9):5215-5223. cited by applicant Arteaga, Carlos L et al (1993) Transforming growth factor beta 1 can induce estrogen-independent tumorigenicity of human breast cancer cells in athymic mice Cell Growth Diff 4(3):193-201. cited by applicant Arteaga, CL et al (1993) Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta Interactions in human breast cancer progression J Clin Invest 92(6):2569-2576. cited by applicant Arteaga, CL (2006) Inhibition of TGFbeta signaling in cancer therapy Curr Opin Genet Dev 16(1):30-37. cited by applicant Banovic, T et al (2005) TGF-beta in allogeneic stem cell transplantation: friend or foe? Blood 106(6):2206-2214. cited by applicant Biswas S et al (2007) Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression J Clin Invest 117(5):1305-1313. cited by applicant Bollard, CM et al (2002) Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity Blood 99(9):3179-3187. cited by applicant Broderick, L et al (2006) Membrane-associated TGF-betal inhibits human memory T cell signaling in malignant and nonmalignant inflammatory microenvironments J Immunol 177(5):3082-3088. cited by applicant Dasch Jr et al (1989) Monoclonal antibodies recognizing transforming growth factor-beta Bioactivity neutralization and transforming growth factor beta 2 affinity purification J Immunol 142(5):1536-1541. cited by applicant Derynck R et al (1986) The murine transforming growth factor-beta precursor. J Biol Chem 261(10):4377-4379. cited by applicant Di Bari, MG et al (2009) TGF-beta modulates the functionality of tumor-infiltrating CD8-+ T cells through effects on TCR signaling and Spred1 expression Cancer Immunol Immunother 58(11):1809-1818. cited by applicant Fong, L et al (2008) Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of Immunomodulatory antibodies for cancer treatment J Clin Oncol 26(32):5275-5283. cited by applicant Garrison, K et al (2012) the small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis.Cancer Immunol Immunothe 61 (4):511-521. cited by applicant Ito, N et al (1995) Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma Cancer Lett 89(1):45-48. cited by applicant Liu, VC et al (2007) Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+T regulatory cells: role of tumor-derived TGF-beta J Immunol 178(5): 2883-2892. cited by applicant Muraoka-Cook, RS et al (2004) Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors Cancer Res 64(24):9002-9011. cited by applicant Nabel, EG et al (1993) Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia Proc Natl Acad Sci 90(22):10759-10763. cited by applicant Nam, JS et al (2008) An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments Cancer Res 68(10):3835-3843. cited by applicant Pasquale, LR et al (1993) Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of hte human eye Invest Ophthalmol Vis Sci 34(1):23-30. cited by applicant Sabbatini, P et al (2012) Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients Clin Cancer Res 18(23):6497-6508. cited by applicant Sato, E et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer Proc Natl Acad Sci USA 102(51):18538-18543. cited by applicant Shah, M et al (1995) Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring J Cell Sci 108(Pt 3):985-1002. cited by applicant Shah, AH et al (2002) Reconstitution of lethally irradiated adult mice with dominant negative TGF-beta type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease J Immunol 169(7):3485-3491. cited by applicant Shariat, Shahrakh F et al (2001) Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy J Clin Oncol 19(11):2856-2864. cited by applicant Shariat, SF et al (2001) Preoperative plasma levels of transforming growth factor beta(1) strongly predict clinical outcome in patients with bladder carcinoma Cancer 92(12):2985-2992. cited by applicant Siegel, Peter M et al (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer Nat Rev Cancer 3(11):807-821. cited by applicant Siegel, PM et al (2003) Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis Proc Natl Acad Sci USA 100(14):8430-8435. cited by applicant Takaku, S et al (2010) Blockade of TGF-beta enhances tumor vaccine efficacy mediated by CD8(+) T cells Int J Cancer 126(7):1666-1674. cited by applicant Teicher, Beverly A et al (1997) Prostate carcinoma response to cytotoxic therapy: in vivo resistance In Vivo 11(6):453-461. cited by applicant Teicher, BA et al (1997) Transforming growth factor-beta 1 overexpression produces drug resistance in vivo: reversal by decorin In Vivo 11(6):463-472. cited by applicant Terabe. M et al (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence J Exp Med 198(11):1741-1752. cited by applicant Terabe, M et al (2009) Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody Clin Cancer Res 15(21):6560-6569. cited by applicant Tsushima, H et al (2001) Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer Clin Cancer Res 7(5):1258-1262. cited by applicant Wojtowicz-Praga, S (2003) Reversal of tumor-induced immunosuppression by TGF-beta inhibitors Invest New Drugs 21(1):21-32. cited by applicant Yang, L et al (2010) Gr-1+CD11b+ myeloid-derived suppressor cells: formidable partners in tumor metastasis J Bone Miner Res 25(8):1701-1706. cited by applicant Zhang, Q et al (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer Cancer Res 65(5):1761-1769. cited by applicant Zhang, Q et al (2006) Blockade of transforming growth factor-{beta} signaling in tumor-reactive CD8(+) T cells activates the antitumor immune response cycle Mol Cancer Ther 5(7):1733-1743. cited by applicant |
| Assistant Examiner: | McCollum, Andrea K |
| Primary Examiner: | Gangle, Brian |
| Attorney, Agent or Firm: | Klauber & Jackson LLC |
| Accession Number: | edspgr.10035851 |
| Database: | USPTO Patent Grants |
| Language: | English |
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