Humanized and variant TGF-β1 specific antibodies and methods and uses thereof
View Patent ↗Antibodies, particularly humanized and variant antibodies and fragments thereof, which bind to TGF-β1 are provided, recognizing human and mouse TGF-β1, particularly that preferentially bind TGF-β1, including which do not recognize or bind TGF-β2 or TGF-β3. Humanized and variant antibodies provided 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, and in fibrotic conditions. The anti-TGF-β1 antibodies, variable regions or CDR domain sequences thereof, and fragments thereof may also be used in lymphoid cell-mediated, including T cell-mediated, therapy and/or combination with chemotherapeutics, immune modulators, or anti-cancer agents and/or with other antibodies or fragments thereof. Particular antibodies are exemplified herein, including antibodies 13A1-2A, 13A1-2B, 13A1-2C, 13A1-2D, 13A1-2E, 13A1-2F, 13A1-2G, 13A1-2H, 13A1-2I, 13A1-2J, 13A1-AF, 13A1-AG, 13A1-AH, 13A1-BF, 13A1-BG, 13A1-BH, 13A1-CF, 13A1-CG, 13A1-CH, 13A1-DF, 13A1-DG, 13A1-DH, 13A1-EF, 13A1-EG and 13A1-EH.
1 . An isolated antibody or antigen-binding fragment thereof which recognizes human and mouse transforming growth factor beta 1 (TGF-β1) and which neutralizes activity of TGF-β1, wherein the antibody or antigen-binding fragment comprises
a heavy chain variable region sequence comprising a CDR1 sequence NYWMH (SEQ ID NO:64), a CDR2 sequence TIYPGNSDTNYNQKFKD (SEQ ID NO:75), and a CDR3 sequence EDSRSLYYNGWDYFDY (SEQ ID NO:9);
and a light chain variable region sequence comprising
a CDR1 sequence KSSESVDNYGISFLN (SEQ ID NO:70) a CDR2 sequence AASNQGS (SEQ ID NO: 31), and a CDR3 sequence QQSKEVPR (SEQ ID NO: 73).
2 . The isolated antibody or antigen-binding fragment of claim 1 which does not recognize or neutralize TGF-β2 or TGF-β3.
3 . The isolated antibody or antigen-binding fragment of claim 1 comprising the heavy chain variable region sequence of SEQ ID NO:18 or variants thereof, wherein said variants comprise at least 90% amino acid identity to the heavy chain variable region sequence comprising SEQ ID NO:18, wherein said variants retain TGF-β1 binding and neutralization.
4 . The antibody or antigen-binding fragment of claim 1 wherein the heavy chain variable region sequence is SEQ ID NO:18.
5 . The isolated antibody or antigen-binding fragment of claim 1 comprising:
(a) the light chain variable region sequence of SEQ ID NO:26 or variants thereof, wherein said variants comprise at least 90% amino acid identity to the light chain variable region sequence comprising SEQ ID NO:26, wherein said variants retain TGF-β1 binding and neutralization; or
(b) the light chain variable region sequence of SEQ ID NO:52 or variants thereof, wherein said variants comprise at least 90% amino acid identity to the light chain variable region sequence comprising SEQ ID NO:52, wherein said variants retain TGF-β1 binding and neutralization.
6 . The antibody of claim 1 wherein the light chain variable region sequence is SEQ ID NO:26 or SEQ ID NO:52.
7 . The isolated antibody of claim 1 which is antibody 13A1-2B comprising the heavy chain variable region sequence of SEQ ID NO:18, and light chain variable region sequence SEQ ID NO:26.
8 . The isolated antibody or antigen-binding fragment of claim 1 which is a humanized or chimeric antibody.
9 . The isolated antibody or antigen-binding fragment of claim 1 which is in the form of a F(ab′)2, scFv fragment, minibody, diabody, triabody or tetrabody.
10 . The isolated antibody or antigen-binding fragment of claim 1 further comprising a detectable or functional label.
11 . The isolated antibody or antigen-binding fragment of claim 10 , wherein said detectable or functional label is a covalently attached drug or a radiolabel.
12 . An isolated nucleic acid which comprises a sequence encoding an antibody or antigen-binding fragment of claim 1 .
13 . A method of preparing an antibody or antigen-binding fragment which comprises expressing the nucleic acid of claim 12 under conditions to bring about expression of said antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment.
14 . A method of treatment of cancer, reducing recurrence of cancer, or treatment of metastasis of cancer in a mammal, wherein TGF-β1 is expressed in the cancer or in a tumor of the cancer, which comprises administering to said mammal an effective amount of an antibody or antigen-binding fragment as defined in claim 1 .
15 . The method of claim 14 further comprising administering a chemotherapeutic agent or immunomodulatory agent.
16 . The method of claim 14 wherein administering is via intratumoral injection.
17 . The method of claim 14 further comprising administering radiation therapy.
18 . A method for stimulating or enhancing an immune response to a vaccine or antigen or an immunomodulatory agent, or enhancing radiation therapy in a mammal which comprises administering to said mammal an effective amount of an antibody or antigen-binding fragment as defined in claim 1 .
19 . The method of claim 18 further comprising administering a chemotherapeutic agent or immunomodulatory agent.
20 . The method of claim 18 wherein administering is via intratumoral injection.
21 . A pharmaceutical composition comprising an antibody or antigen-binding fragment as defined in claim 1 and a pharmaceutically acceptable vehicle, carrier or diluent.
22 . An immunological composition comprising an antibody or antigen-binding fragment as defined in claim 1 and a pharmaceutically acceptable vehicle, carrier or diluent, and further comprising an adjuvant, one or more antigen, an immunoregulatory antibody, or a small molecule inhibitor to an immune modulator.
23 . Lymphoid cells genetically engineered to express and secrete the antibody or antigen-binding fragment according to claim 1 .
24 . The lymphoid cells of claim 23 wherein said cells are further engineered to express receptors.
25 . The lymphoid cells of claim 24 wherein said receptor is a chimeric antigen receptor (CAR).
26 . The lymphoid cells of claim 24 wherein said receptor is a T cell receptor.
27 . The lymphoid cells of claim 23 wherein said cells are further engineered to express and secrete one or more soluble proteins.
28 . A method of treatment of cancer, reducing recurrence of cancer, or treatment of metastasis of cancer in a mammal, wherein TGF-β1 is expressed in the cancer or in a tumor of the cancer, which comprises administering to said mammal the genetically engineered lymphoid cells of claim 23 for adoptive cell therapy (ACT).