WO2021039945A1 - Cross-species anti-latent tgf-beta 1 antibodies and methods of use - Google Patents
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- WO2021039945A1 WO2021039945A1 PCT/JP2020/032522 JP2020032522W WO2021039945A1 WO 2021039945 A1 WO2021039945 A1 WO 2021039945A1 JP 2020032522 W JP2020032522 W JP 2020032522W WO 2021039945 A1 WO2021039945 A1 WO 2021039945A1
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Abstract
Description
[PTL 2] WO 2016115345
[PTL 3] WO 2017156500
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A1. An anti-latent TGF-
(a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:20, 21 and 22, respectively;
(b) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:26, 27 and 28, respectively;
(c) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:32, 33 and 34, respectively; or
(d) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:38, 39 and 40, respectively.
A2. The anti-latent TGF-
(a) HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:23, 24 and 25, respectively;
(b) HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:29, 30 and 31, respectively;
(c) HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:35, 36 and 37, respectively; and
(d) HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:41, 42 and 43, respectively.
A3. An anti-latent TGF-
(a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:20, 21 and 22, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:23, 24 and 25, respectively;
(b) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:26, 27 and 28, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:29, 30 and 31, respectively;
(c) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:32, 33 and 34, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:35, 36 and 37, respectively; or
(d) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:38, 39 and 40, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:41, 42 and 43, respectively.
A4. The anti-latent TGF-
(a) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:12, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:13, or (iii) a VH sequence as in (i) and a VL sequence as in (ii);
(b) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:14, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15, or (iii) a VH sequence as in (i) and a VL sequence as in (ii);
(c) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:17, or (iii) a VH sequence as in (i) and a VL sequence as in (ii); or
(d) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:18, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19, or (iii) a VH sequence as in (i) and a VL sequence as in (ii).
A5. The anti-latent TGF-
A6. The anti-latent TGF-
A7. The anti-latent TGF-
(a) a VH sequence of SEQ ID NO:12 and a VL sequence of SEQ ID NO:13;
(b) a VH sequence of SEQ ID NO:14 and a VL sequence of SEQ ID NO:15;
(c) a VH sequence of SEQ ID NO:16 and a VL sequence of SEQ ID NO:17; or
(d) a VH sequence of SEQ ID NO:18 and a VL sequence of SEQ ID NO:19.
A8. An anti-latent TGF-
(a) a VH sequence of SEQ ID NO:12 and a VL sequence of SEQ ID NO:13;
(b) a VH sequence of SEQ ID NO:14 and a VL sequence of SEQ ID NO:15;
(c) a VH sequence of SEQ ID NO:16 and a VL sequence of SEQ ID NO:17; or
(d) a VH sequence of SEQ ID NO:18 and a VL sequence of SEQ ID NO:19.
A9. The anti-latent TGF-
A10. The anti-latent TGF-
A11. The anti-latent TGF-
A12. The anti-latent TGF-
A13. The anti-latent TGF-
A14. The anti-latent TGF-
A15. The anti-latent TGF-
A16. The anti-latent TGF-
A17. The anti-latent TGF-
A18. The anti-latent TGF-
A19. The anti-latent TGF-
A20. The anti-latent TGF-
A21. An anti-latent TGF-
(a) a full length heavy chain sequence of SEQ ID NO:47 and a full length light chain sequence of SEQ ID NO:60;
(b) a full length heavy chain sequence of SEQ ID NO:48 and a full length light chain sequence of SEQ ID NO:61;
(c) a full length heavy chain sequence of SEQ ID NO:49 and a full length light chain sequence of SEQ ID NO:62;
(d) a full length heavy chain sequence of SEQ ID NO:50 and a full length light chain sequence of SEQ ID NO:63;
(e) a full length heavy chain sequence of SEQ ID NO:51 and a full length light chain sequence of SEQ ID NO:64;
(f) a full length heavy chain sequence of SEQ ID NO:52 and a full length light chain sequence of SEQ ID NO:65;
(g) a full length heavy chain sequence of SEQ ID NO:53 and a full length light chain sequence of SEQ ID NO:66; or
(h) a full length heavy chain sequence of SEQ ID NO:54 and a full length light chain sequence of SEQ ID NO:67.
A22. The anti-latent TGF-
A23. The anti-latent TGF-
A24. The anti-latent TGF-
A25. An immunoconjugate comprising the anti-latent TGF beta-1 antibody of any one of A1 to A24 and a cytotoxic agent.
A26. An isolated nucleic acid encoding the anti-latent TGF beta-1 antibody of any one of A1 to A24.
A27. A vector comprising the nucleic acid of A26.
A28. A host cell comprising the nucleic acid of A26 or the vector of A27.
A29. A method of producing an anti-latent TGF beta-1 antibody comprising culturing the host cell of A28 so that the antibody is produced.
A30. The method of A29, further comprising recovering the antibody from the host cell.
B1. The anti-latent TGF beta-1 antibody of any one of A1 to A24 or the immunoconjugate of A25, for use as a medicament.
B2. The anti-latent TGF beta-1 antibody of any one of A1 to A24 or the immunoconjugate of A25, for use in treating fibrosis or cancer.
B3. Use of the anti-latent TGF beta-1 antibody of any one of A1 to A24 or the immunoconjugate of A25, in the manufacture of a medicament for treatment of fibrosis or cancer.
B4. The anti-latent TGF beta-1 antibody of any one of A1 to A24 or the immunoconjugate of A25, for use in combination with an additional therapeutic agent, preferably an immune checkpoint inhibitor, for treatment of cancer.
B5. The anti-latent TGF beta-1 antibody or the immunoconjugate of B4, wherein the immune checkpoint inhibitor is a PD-1 axis binding antagonist, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
B6. The anti-latent TGF beta-1 antibody or the immunoconjugate of B4, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.
B7. The anti-latent TGF beta-1 antibody or the immunoconjugate of any one of B4 to B6, wherein the immune checkpoint inhibitor is administered concomitantly with the anti-latent TGF beta-1 antibody or the immunoconjugate.
B8. The anti-latent TGF beta-1 antibody or the immunoconjugate of any one of B4 to B6, wherein the immune checkpoint inhibitor is administered before or after the administration of the anti-latent TGF beta-1 antibody or the immunoconjugate.
C1. A pharmaceutical formulation comprising the anti-latent TGF beta-1 antibody of any one of A1 to A24 or the immunoconjugate of A25, and a pharmaceutically acceptable carrier.
C2. The pharmaceutical formulation of C1, further comprising an additional therapeutic agent, preferably an immune checkpoint inhibitor.
C3. The pharmaceutical formulation of C2, wherein the immune checkpoint inhibitor is a PD-1 axis binding antagonist, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
C4. The pharmaceutical formulation of C2, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.
C5. The pharmaceutical formulation of any one of C1 to C4, for use in treatment of fibrosis or cancer.
C6. The pharmaceutical formulation of any one of C1 to C4, for use in combination with an additional therapeutic agent, preferably an immune checkpoint inhibitor, for treatment of cancer.
C7. The pharmaceutical formulation of C6, wherein the immune checkpoint inhibitor is a PD-1 axis binding antagonist, preferably an anti-PD1 antibody or an anti-PD-L1 antibody.
C8. The pharmaceutical formulation of C6, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.
C9. The pharmaceutical formulation of any one of C6 to C8, wherein the immune checkpoint inhibitor is administered concomitantly with the pharmaceutical formulation.
C10. The pharmaceutical formulation of any one of C6 to C8, wherein the immune checkpoint inhibitor is administered before or after the administration of the pharmaceutical formulation.
D1. A pharmaceutical formulation comprising an immune checkpoint inhibitor and a pharmaceutically acceptable carrier, for use in combination with the anti-latent TGF beta-1 antibody of any one of Claim A1 to A24 or the immunoconjugate of Claim A25, for treatment of cancer.
D2. The pharmaceutical formulation of D1, wherein the immune checkpoint inhibitor is a PD-1 axis binding antagonist, preferably an anti-PD1 antibody or an anti-PD-L1 antibody.
D3. The pharmaceutical formulation of D1, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.
D4. The pharmaceutical formulation of any one of D1 to D3, wherein wherein the anti-latent TGF beta-1 antibody or the immunoconjugate is administered concomitantly with the pharmaceutical formulation.
D5. The pharmaceutical formulation of any one of D1 to D3, wherein the anti-latent TGF beta-1 antibody or the immunoconjugate is administered before or after the administration of the pharmaceutical formulation.
E1. A method of treating an individual having fibrosis or cancer comprising administering to the individual an effective amount of the anti-latent TGF beta-1 antibody of any one of A1 to A24 or the immunoconjugate of A25.
E2. The method of E1 further comprising administering an additional therapeutic agent, preferably an immune checkpoint inhibitor, to the individual.
E3. The method of E1 or E2, wherein the immune checkpoint inhibitor is a PD-1 axis binding antagonist, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
E4. The method of E3, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.
E5. The method of any one of E1 to E4, wherein the immune checkpoint inhibitor is administered concomitantly with the anti-latent TGF beta-1 antibody or the immunoconjugate.
E6. The method of any one of E1 to E4, wherein the immune checkpoint inhibitor is administered before or after the administration of the anti-latent TGF beta-1 antibody or the immunoconjugate.
An "acceptor human framework" for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
(a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));
(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));
(c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); and
(d) combinations of (a), (b), and/or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).
Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.
100 times the fraction X/Y
where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.
In one aspect, the invention is based, in part, on anti-latent TGF-
In one aspect, the invention provides isolated antibodies that bind to latent TGF-
In one aspect, an anti-latent TGF-
binds to latent TGF-
binds to latent TGF-
binds to latent TGF-
binds to latent TGF-
binds to cell surface latent TGF-
binds to LAP region of latent TGF-
binds to LAP;
binds to latent TGF-
inhibits protease mediated release of mature TGF-
does not inhibit protease mediated cleavage of LAP region of latent TGF-
does not or does not significantly inhibit integrin mediated release of mature TGF-
causes reduced or fewer toxicities and/or adverse effects associated with anti-TGF-
In further embodiments, the anti-latent TGF-
a monoclonal antibody;
a human, humanized or chimeric antibody;
a full length of IgG antibody; and/or
an antibody fragment.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37.
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43.
(1) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25;
(2) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31;
(3) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37; or
(4) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43.
(1) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25;
(2) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31;
(3) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37; or
(4) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43.
(1) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25;
(2) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31;
(3) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37; or
(4) An anti-latent TGF-
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43.
In certain embodiments, an antibody provided herein has a dissociation constant (KD) of 1 micromolar or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g. 10-8 M or less, e.g. from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M).
In certain embodiments, an antibody provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For discussion of Fab and F(ab')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.
In certain embodiments, an antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
In certain embodiments, an antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).
Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, e.g., in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132(2004).
In certain embodiments, an antibody provided herein is a multispecific antibody, e.g. a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for TGF-
In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding activity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.
In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Conservative substitutions are shown in Table 1 under the heading of "preferred substitutions." More substantial changes are provided in Table 1 under the heading of "exemplary substitutions," and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
(1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;
(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;
(3) acidic: Asp, Glu;
(4) basic: His, Lys, Arg;
(5) residues that influence chain orientation: Gly, Pro;
(6) aromatic: Trp, Tyr, Phe.
Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
In certain embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions. In another embodiment, a human Fc variant may comprise a chimeric human Fc region sequence (e.g., a human IgG1/4 or human IgG2/4 Fc region), or a chimeric human Fc region sequence which further comprises an amino acid modification (e.g. a substitution) at one or more amino acid positions.
In certain embodiments, it may be desirable to create cysteine engineered antibodies, e.g., "thioMAbs," in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, e.g., in U.S. Patent No. 7,521,541.
In certain embodiments, an antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.
Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567. In one embodiment, isolated nucleic acid encoding an anti-latent TGF-
Anti-latent TGF-
In one aspect, an antibody of the invention is tested for its antigen binding activity, e.g., by known methods such as ELISA, Western blot, surface plasmon resonance (e.g. BIACORE(registered trademark)) or a similar technique (e.g. KinExa or OCTET(registered trademark)), etc.
In one aspect, assays are provided for identifying anti-latent TGF-
diet (CDAHFD)-induced NASH/liver fibrosis mouse model, a bleomycin (BLM)- induced lung fibrosis mouse model, and/or a syngeneic tumor model (e.g., as described in Mariathasan S et al., TGF-beta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018 Feb 22;554(7693):544-548.). In further embodiments, the anti-latent TGF-
In one aspect, a method for screening an antibody of the invention comprises various assays described herein and known in the art. For example, a method for screening an anti-latent TGF-
(a) contacting a biological sample comprising latent TGF-
(b) detecting (i) whether a test antibody inhibits the cleavage of the LAP region of latent TGF-
(c) selecting the test antibody that inhibits activation of latent TGF-
(b) measuring (i) the amount of non-cleaved latent TGF-
(c) selecting the test antibody that inhibits a protease mediated release of mature TGF-
Alternatively, rather than steps (b) and (c) above, the method for screening an anti-latent TGF-
(b) measuring (i) the amount of cleavage product of latent TGF-
(c) selecting the test antibody that inhibits a protease mediated activation of latent TGF-
Furthermore, the present invention provides a method for producing an anti-latent TGF-
(d) obtaining amino acid sequence information of the anti-latent TGF-
(e) introducing a gene encoding the anti-latent TGF-
The invention also provides immunoconjugates comprising an anti-latent TGF-
In certain embodiments, any of the anti-latent TGF-
(a) contacting a biological sample with an anti-latent TGF-
(b) detecting whether a complex is formed between the anti-latent TGF-
Pharmaceutical formulations of an anti-latent TGF-
Any of the anti-latent TGF-
In another aspect of the invention, an article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above (e.g., fibrosis and cancer) is provided. The article of manufacture comprises a container and a label on or a package insert associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition (e.g., fibrosis and cancer) and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active ingredient in the composition is an antibody or immunoconjugate of the invention. The label or package insert indicates that the composition is used for treating the condition of choice (e.g., fibrosis and cancer). Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody/immunoconjugate of the invention; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition (e.g., fibrosis and cancer). Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
The present disclosure provides kits for use in a method for the treatment, prevention and/or diagnosis of the disorders described herein, in particular, treatment of an individual having fibrosis or cancer, which contain an anti-latent TGF-
(1-1) Expression and purification of latent TGF-
The sequences used for expression and purification were: flag-tagged human latent TGF-beta 1 (SEQ ID NO: 1, 2) and flag-tagged mouse latent TGF-beta 1 (SEQ ID NO: 3, 4), and flag-tagged cynomolgus monkey latent TGF-beta 1 (SEQ ID NO: 5, 6). Each of these flag-tagged latent TGF-
The sequence used for expression and purification was: flag-tagged mouse LAP (SEQ ID NO: 8, 9), which has, from its N-terminus to C terminus, a signal sequence derived from rat serum albumin (SEQ ID NO: 7), a Flag-tag, and a sequence of latency associated protein (LAP). The Cys residue at the thirtieth (30th) position in flag-tagged LAP was substituted with Ser, which corresponds to 'C33S mutation'. Expression and purification of Flag-tagged mouse LAP (SEQ ID NO: 8, 9) (hereinafter called "recombinant mouse latency associated protein (LAP)") were performed exactly the same way as described in EXAMPLE (1-1).
(2-1) Humanization
A parent anti-TGF-beta antibody TBA0947, chimeric antibody, was humanized as follows. First, variable regions of the heavy and light chains of humanized antibodies were designed using variable regions of TBA0947 and human germline frameworks. Then, the polynucleotides of each designed heavy variable region and light chain variable region were cloned into expression vectors containing the heavy chain constant region SG181 sequence (SEQ ID NO: 10) and the light chain constant region SK1 sequence (SEQ ID NO: 11), respectively. Humanized antibodies were transiently expressed in FreeStyle 293-F Cells (Thermo Fisher Scientific), and Biacore analysis was carried out. A humanized antibody that showed at least similar Biacore binding activity as the parent antibody was selected.
The humanized antibody obtained in Example (2-1) was optimized to hT0947AE04, hT0947AE07, hT0947AE08, and hT0947AE09 with improved binding activity towards latent TGF-beta 1 (SLC). Briefly, comprehensive mutagenesis was performed for all residues in the complementarity-determining regions (CDRs) of both heavy and light chain. Each amino acid was substituted with 18 other naturally occurring amino acids, excluding the original amino acid and cysteine. The variants were transiently expressed in FreeStyle 293-F Cells (Thermo Fisher Scientific), and purified from culture supernatants for assessment by Biacore. Variants of interest with improved binding activity to both human and murine latent TGF-beta 1 (SLC) were selected. Antibodies with a combination of these mutations in the CDRs were then generated.
The amino acid sequences of the variable regions of hT0947AE04, hT0947AE07, hT0947AE08, and hT0947AE09 were identified as follows:
- The heavy chain variable region of hT0947AE04 comprises an amino acid sequence of SEQ ID NO: 12 (hT0947AE04H), and the light chain variable region of hT0947AE04 comprises an amino acid sequence of SEQ ID NO: 13 (hT0947AE04L).
- The heavy chain variable region of hT0947AE07 comprises an amino acid sequence of SEQ ID NO: 14 (hT0947AE07H), and the light chain variable region of hT0947AE07 comprises an amino acid sequence of SEQ ID NO: 15 (hT0947AE07L).
- The heavy chain variable region of hT0947AE08 comprises an amino acid sequence of SEQ ID NO: 16 (hT0947AE08H) and the light chain variable region of hT0947AE08 comprises an amino acid sequence of SEQ ID NO: 17 (hT0947AE08L).
- The heavy chain variable region of hT0947AE09 comprises an amino acid sequence of SEQ ID NO: 18 (hT0947AE09H), and the light chain variable region of hT0947AE09 comprises an amino acid sequence of SEQ ID NO: 19 (hT0947AE09L).
- hT0947AE04 comprises the heavy chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 20, 21 and 22, respectively, and the light chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 23, 24 and 25, respectively.
- hT0947AE07 comprises the heavy chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 26, 27 and 28, respectively, and the light chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 29, 30 and 31, respectively.
- hT0947AE08 comprises the heavy chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 32, 33 and 34, respectively, and the light chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 35, 36 and 37, respectively.
- hT0947AE09 comprises the heavy chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 38, 39 and 40, respectively, and the light chain CDR1, CDR2 and CDR3 which comprise amino acid sequences of SEQ ID NOs: 41, 42 and 43, respectively.
Multiple amino acid substitutions were introduced to a heavy chain constant region SG1 (SEQ ID NO: 44). SG1 is a wild-type human IgG1 heavy chain constant region with the deletion of the last two C-terminal amino acids, Gly-Lys (GK). As a result, SG181 (SEQ ID NO: 10) and SG191 (SEQ ID NO: 45) were generated. SG181 includes amino acid substitutions L235R/G236R (amino acid substitutions to reduce effector function), and K214R, according to the EU index. SG191 includes amino acid substitutions L235R/G236R (amino acid substitutions to reduce effector function), M428L/N434A (amino acid substitutions to enhance binding activity to FcRn), Q438R/S440E (amino acid substitutions to reduce binding to rheumatoid factor), and K214R, according to the EU index. Further, mF18 (SEQ ID NO: 46), a mouse IgG heavy chain constant region which includes P235K/S239K (amino acid substitutions to reduce effector function), was generated.
(a1) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 47, which comprises hT0947AE04H (heavy chain variable region) and SG181 (heavy chain constant region)
(a2) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 48, which comprises hT0947AE07H (heavy chain variable region) and SG181 (heavy chain constant region)
(a3) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 49, which comprises hT0947AE08H (heavy chain variable region) and SG181 (heavy chain constant region)
(a4) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 50, which comprises hT0947AE09H (heavy chain variable region) and SG181 (heavy chain constant region)
(b1) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 51, which comprises hT0947AE04H (heavy chain variable region) and SG191 (heavy chain constant region)
(b2) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 52, which comprises hT0947AE07H (heavy chain variable region) and SG191 (heavy chain constant region)
(b3) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 53, which comprises hT0947AE08H (heavy chain variable region) and SG191 (heavy chain constant region)
(b4) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 54, which comprises hT0947AE09H (heavy chain variable region) and SG191 (heavy chain constant region)
(c1) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 55, which comprises hT0947AE04H (heavy chain variable region) and mF18 (heavy chain constant region)
(c2) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 56, which comprises hT0947AE07H (heavy chain variable region) and mF18 (heavy chain constant region)
(c3) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 57, which comprises hT0947AE08H (heavy chain variable region) and mF18 (heavy chain constant region)
(c4) The full-length heavy chain comprising an amino acid sequence of SEQ ID NO: 58, which comprises hT0947AE09H (heavy chain variable region) and mF18 (heavy chain constant region)
(d1) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 60, which comprises hT0947AE04L (light chain variable region) and SK1 (light chain constant region)
(d2) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 61, which comprises hT0947AE07L (light chain variable region) and SK1 (light chain constant region)
(d3) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 62, which comprises hT0947AE08L (light chain variable region) and SK1 (light chain constant region)
(d4) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 63, which comprises hT0947AE09L (light chain variable region) and SK1 (light chain constant region)
(e1) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 64, which comprises hT0947AE04L (light chain variable region) and mk1 (light chain constant region)
(e2) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 65, which comprises hT0947AE07L (light chain variable region) and mk1 (light chain constant region)
(e3) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 66, which comprises hT0947AE08L (light chain variable region) and mk1 (light chain constant region)
(e4) The full-length light chain comprising an amino acid sequence of SEQ ID NO: 67, which comprises hT0947AE09L (light chain variable region) and mk1 (light chain constant region)
Binding activities of anti-latent TGF-
Binding activities (ka, kd and KD) of anti-latent TGF-
(4-1) Anti-latent TGF-
Binding activities of anti-latent TGF-
Binding activities of anti-latent TGF-
Further, binding activities of anti-latent TGF-
Mouse latent TGF-beta 1 (mSLC) and human latent TGF-beta 1 (hSLC), which were prepared in Example (1-1), were each incubated with or without the presence of anti-latent TGF-
As shown in Figure 3, spontaneous activation of latent TGF-
Mouse latent TGF-beta 1 (mSLC) and human latent TGF-beta 1 (hSLC) , which were prepared in Example (1-1), were each incubated with human plasmin (Calbiochem), with or without the presence of anti-latent TGF-
Mouse latent TGF-beta 1 (mSLC) and human latent TGF-beta 1 (hSLC) , which were prepared in Example (1-1), were each incubated with human kallikrein (Enzyme Research Laboratories), with or without the presence of anti-latent TGF-
Human latent TGF-beta 1 (SLC), which were prepared in Example (1-1), was incubated with activated metalloproteinase 2 (MMP2) or MMP9 (R&D systems), with or without the presence of anti-latent TGF-
Mouse latent TGF-beta 1 (mSLC) and human latent TGF-beta 1 (hSLC), which were prepared in Example (1-1), were each incubated with human plasmin (Calbiochem), with or without the presence of anti-latent TGF-
As shown in Figure 7, latent TGF-
Mouse PBMC and HEK-BlueTM TGF-beta cell co-culture assay was conducted to detect integrin-mediated latent TGF-
As shown in Figure 8, anti-latent TGF-
The in vivo efficacy of anti-latent TGF-
The EMT6 murine mammary carcinoma cell line was obtained from American Type Culture Collection (ATCC CRL-2755). Cells were cultured in RPMI-1640 medium (SIGMA) plus 2 mM L-glutamine (SIGMA) with 10% fetal bovine serum (FBS; SIGMA). Specific pathogen-free Balb/c female mice of 6 weeks of age were purchased from Japan Charles River Inc. and were acclimated for 2 week before the inoculation. EMT6 cells in log-phase growth were harvested and washed with Hank's balanced salt solution (HBSS; SIGMA), re-suspended in 50% HBSS and 50% Matrigel (CORNING) at a concentration of
When mean tumor volume reached about 100-300 mm3 (7 days after inoculation), mice were randomized into groups based on tumor volume and body weight. Tumor volume was measured with caliper, and tumor volume was calculated as follows:
Tumor volume (mm3) = (1/2) x length (mm) x width (mm)2
Following the establishment of the mouse model in Example (5-1), mice were treated with isotype control antibodies (mouse IgG1 antibody in combination with rat IgG2b antibody, purchased from Bio X Cell), anti-mouse PD-L1 antibody (rat IgG2b clone 10F.9G2, purchased from Bio X Cell), hT0947AE04-mF18 or a combination of hT0947AE04-mF18 with the anti-mouse PD-L1 antibody, as shown in Table 4. Antibodies were administered 3 times a week for 3 weeks. The first dose was administered intravenously, and the second dose and thereafter were administered intraperitoneally.
TGI[%] = {1-(T-T0)/(C-C0)} x 100
wherein 'T' is the mean tumor volume of the Group on the day of measurement, 'T0' is the mean tumor volume of the Group on the day of randomization, 'C' is the mean tumor volume of Group 1 (isotype control) on the day of measurement, and 'C0' is the mean tumor volume of the Group 1 (isotype control) on the day of randomization.
As a result, values of TGI[%] of anti-mouse PD-L1 antibody (Group 2), hT0947AE04-mF18 (Group 3) and the combination of hT0947AE04-mF18 with anti-mouse PD-L1 antibody (Group 4) on the 14th day after the first dose were 51, 12 and 83, respectively. Therefore, synergistic antitumor effect between anti-latent TGF-beta 1 (hT0947AE04-mF18) and anti-PD-L1 antibody was observed.
The in vivo efficacies of anti-latent TGF-
The EMT6 murine mammary carcinoma cell line was obtained from American Type Culture Collection (ATCC CRL-2755). Cells were cultured in RPMI-1640 medium (SIGMA) plus 2 mM L-glutamine (SIGMA) with 10% fetal bovine serum (FBS; SIGMA). Specific pathogen-free Balb/c female mice of 7 weeks of age were purchased from Japan Charles River Inc. and were acclimated for 1 week before the inoculation. EMT6 cells in log-phase growth were harvested and washed with Hank's balanced salt solution (HBSS; SIGMA), resuspended in 50% HBSS and 50% Matrigel (CORNING) at a concentration of
When mean tumor volume reached about 100-300 mm3 (7 days after inoculation), mice were randomized into groups based on tumor volume and body weight. Tumor volume was measured with caliper, and tumor volume was calculated as follows:
Tumor volume (mm3) = (1/2) x length (mm) x width (mm)2
Following the establishment of the mouse model in Example (6-1), mice were treated with vehicle (150 mM NaCl/20 mM His-HCl buffer pH6.0), anti-mouse PD-L1 antibody (rat IgG2b clone 10F.9G2, purchased from Bio X Cell), a combination of hT0947AE04-mF18 with the anti-mouse PD-L1 antibody, a combination of hT0947AE07-SG181 with the anti-mouse PD-L1 antibody or a combination of hT0947AE08-SG181 with the anti-mouse PD-L1 antibody as shown in Table 5. Antibodies were administered 3 times a week for 3 weeks. The first dose was administered intravenously, and the second dose and thereafter were administered intraperitoneally.
TGI[%] of anti-mouse PD-L1 antibody alone (Group 2), the combination of hT0947AE04-mF18 with anti-mouse PD-L1 antibody (Group 3), the combination of hT0947AE07-SG181 with anti-mouse PD-L1 antibody (Group 4) and the combination of hT0947AE08-SG181 with anti-mouse PD-L1 antibody (Group 5) on the 14th day after the first dose were 64, 89, 86 and 76, respectively. Therefore, anti-latent TGF-
The in vivo efficacy of monoclonal antibodies hT0947AE04-SG191, hT0947AE07-SG191, and hT0947AE08-SG191 were evaluated in Unilateral Ureteral Obstruction (UUO) mouse model which is known to induce a progressive renal fibrosis.
The in vivo efficacies of monoclonal antibodies hT0947AE04-SG191, hT0947AE07-SG191, and hT0947AE08-SG191 were evaluated in Unilateral Ureteral Obstruction (UUO) mouse model which induces a progressive renal fibrosis.
Specific pathogen-free C57BL/6NTac male mice of 6 weeks of age were purchased from Invivos Pte Ltd (Singapore) and were acclimated for 1 weeks before the start of treatments. Animals were maintained at 20 to 26 degree C with a 12:12 hour light/dark cycle and fed with a commercial standard diet (5P75; PMI Nutrition INT'L (LabDiet), Missouri, United States) and tap water ad libitum.
UUO surgery was operated under isoflurane anesthetized condition. The left side of the abdomen was shaved and a vertical incision was made through the skin. A second incision was made through the peritoneum and that skin was also retracted to reveal the kidney. Using forceps, the kidney was brought to the surface and the left ureter was tied with surgical silk, twice, below the kidney. The ligated kidney was placed gently back into its correct anatomical position then peritoneum and skin were sutured. Analgesic agent was added to reduce animal affliction. In the sham operated group, peritoneum and skin were only incised and sutured.
All monoclonal antibodies were administered at 15 mg/kg by intravenous injection three times a week starting from one day before the surgical operation. Anti-KLH antibody (IC17dk-SG181) was used as a negative control in this study. The sham operated group was administered Anti-KLH antibody (IC17dk-SG181). The animals were weighed and then killed by exsanguination under
The hydroxyproline contents in kidney, which is one of the amino acids included in collagen, was measured to evaluate the extramatrix deposition to the tissue. Wet kidney tissues were dried up at 95 degree C for 3 hours and weighed. Then, 6N HCl (100 microliter/1mg dry tissue) was added to the dried tissue and boiled at overnight. Samples were cleaned up by the filter and 10 microliter of each sample was plated into the 96-well plate. The plate with samples was dried out at 60 degree C and hydroxyproline was measured using hydroxyproline assay kit (BioVision). The results of this experiment are shown in Figure 12. Significant increase in hydroxyproline content was observed in disease induced kidney, and all antibodies (hT0947AE04-SG191, hT0947AE07-SG191, and hT0947AE08-SG191) inhibited kidney fibrosis. Data are presented as mean +/- standard error of the mean (SEM). Statistical analysis was performed using analysis of Student's t-test. When P values were <0.05, differences were considered significant.
Potential toxicity of anti-latent TGF-
(Table 6) Summary of Toxicology Studies
In the mouse 3-month study (IV; 5, or 20 mg/kg, Q2D, 46 doses in total), anemic changes (at 20 mg/kg in the hT0947AE04-mF18 group; at 5 and 20 mg/kg in GC1008-mF18 groups) and cardiac lesions (at 5 and 20 mg/kg in GC1008-mF18 groups; see Table 7) were observed. These findings were considered to be caused by on-target toxicities of TGF-beta inhibition. Considering the on-target toxicities in the mouse 3-month study, the NOAEL for hT0947AE04-mF18 was 5 mg/kg IV Q2D. In addition, because the adverse effects for GC1008-mF18 at 5 mg/kg group, the NOAEL for GC1008-mF18 was not determined in the condition of the mouse 3-month study.
(Table 7) Major Findings in Histopathology of Mouse 3-month Toxicity Study
In the monkey 6-week study (IV; 10, 30, or 100 mg/kg, Q2W, 4 doses in total), no toxicologically relevant changes attributable to IV administration of hT0947AE07-SG191 were observed, and the NOAEL was the highest tested dose of 100 mg/kg Q2W.
The in vivo efficacy of anti-latent TGF-
The EMT6 murine mammary carcinoma cell line was obtained from American Type Culture Collection. Cells were cultured in RPMI-1640 medium (SIGMA) with 10% fetal bovine serum (FBS; Nichirei Biosciences Inc). Specific pathogen-free Balb/c female mice of 6 weeks of age were purchased from Japan Charles River Inc. and were acclimated for 1 week before the inoculation. EMT6 cells in log- phase growth were harvested and washed with Hank's balanced salt solution (HBSS; SIGMA), resuspended in 50% HBSS and 50% Matrigel (CORNING) at a concentration of
When mean tumor volume reached about 100-300 mm3 (7days after inoculation), mice were randomized into groups based on tumor volume and body weight. Tumor volume was measured with caliper, and tumor volume was calculated as 1/2 x l x w2 , l=length, w=width.
Mice were treated with vehicle (150 mM NaCl/20 mM His-HCl buffer pH6.0), anti-mouse PD-L1 antibody (rat IgG2b clone 10F.9G2, purchased from Bio X cell, 10 mg/kg first dose followed by 5 mg/kg thereafter), a combination of hT0947AE07-SG191 (10 mg/kg) with anti-mouse PD-L1 antibody or a combination of hT0947AE07-SG191 (30 mg/kg) with anti-mouse PD-L1 antibody. Antibodies were administered 3 times a week for 2 weeks, intravenously for the first dose and intraperitoneally thereafter.
Tumor volume was measured twice a week. Anti-tumor activity was evaluated by tumor growth inhibition (TGI[%]) which was calculated as {1-(T-T0)/(C-C0)} x 100, where the mean tumor volumes for the groups were T on the day of measurement and T0 on the day of randomization, likewise represented by C and C0 for the vehicle control group.
The results of this experiment is shown in Figure 13.
TGI[%] of anti-mouse PD-L1 antibody alone, combination of hT0947AE07-SG191(10 mg/kg) with anti-mouse PD-L1 antibody, and combination of hT0947AE07-SG191(30 mg/kg) with anti-mouse PD-L1 antibody on 14 days after first dose were 60, 77 and 80, respectively. hT0947AE07-SG191 showed combinatorial efficacy with anti-mouse PD-L1 antibody.
Claims (15)
- An anti-latent TGF-beta 1 antibody comprising:
(a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:20, 21 and 22, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:23, 24 and 25, respectively;
(b) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:26, 27 and 28, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:29, 30 and 31, respectively;
(c) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:32, 33 and 34, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:35, 36 and 37, respectively; or
(d) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NO:38, 39 and 40, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NO:41, 42 and 43, respectively. - The anti-latent TGF-beta 1 antibody of Claim 1, comprising:
(a) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:12, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:13, or (iii) a VH sequence as in (i) and a VL sequence as in (ii);
(b) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:14, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15, or (iii) a VH sequence as in (i) and a VL sequence as in (ii);
(c) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:17, or (iii) a VH sequence as in (i) and a VL sequence as in (ii); or
(d) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:18, (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19, or (iii) a VH sequence as in (i) and a VL sequence as in (ii). - An anti-latent TGF-beta 1 antibody comprising:
(a) a VH sequence of SEQ ID NO:12 and a VL sequence of SEQ ID NO:13;
(b) a VH sequence of SEQ ID NO:14 and a VL sequence of SEQ ID NO:15;
(c) a VH sequence of SEQ ID NO:16 and a VL sequence of SEQ ID NO:17; or
(d) a VH sequence of SEQ ID NO:18 and a VL sequence of SEQ ID NO:19. - The anti-latent TGF-beta 1 antibody of any one of Claims 1 to 3, which is a human, humanized, or chimeric antibody.
- The anti-latent TGF-beta 1 antibody of any one of Claims 1 to 4, which is a full length IgG antibody, preferably a full length IgG1 antibody.
- The anti-latent TGF-beta 1 antibody of any one of Claims 1 to 5, wherein the anti-latent TGF-beta 1 antibody comprises a modified IgG1 Fc region having reduced effector function compared with a wild type IgG1 Fc region.
- An anti-latent TGF-beta 1 antibody comprising:
(a) a full length heavy chain sequence of SEQ ID NO:47 and a full length light chain sequence of SEQ ID NO:60;
(b) a full length heavy chain sequence of SEQ ID NO:48 and a full length light chain sequence of SEQ ID NO:61;
(c) a full length heavy chain sequence of SEQ ID NO:49 and a full length light chain sequence of SEQ ID NO:62;
(d) a full length heavy chain sequence of SEQ ID NO:50 and a full length light chain sequence of SEQ ID NO:63;
(e) a full length heavy chain sequence of SEQ ID NO:51 and a full length light chain sequence of SEQ ID NO:64;
(f) a full length heavy chain sequence of SEQ ID NO:52 and a full length light chain sequence of SEQ ID NO:65;
(g) a full length heavy chain sequence of SEQ ID NO:53 and a full length light chain sequence of SEQ ID NO:66; or
(h) a full length heavy chain sequence of SEQ ID NO:54 and a full length light chain sequence of SEQ ID NO:67. - An immunoconjugate comprising the anti-latent TGF beta-1 antibody of any one of Claims 1 to 7 and a cytotoxic agent.
- An isolated nucleic acid encoding the anti-latent TGF beta-1 antibody of any one of Claims 1 to 7.
- A vector comprising the nucleic acid of Claim 9.
- A host cell comprising the nucleic acid of Claim 9 or the vector of Claim 10.
- A method of producing an anti-latent TGF beta-1 antibody comprising culturing the host cell of Claim 11 so that the antibody is produced.
- A pharmaceutical formulation comprising the anti-latent TGF beta-1 antibody of any one of Claims 1 to 7 or the immunoconjugate of Claim 8, and a pharmaceutically acceptable carrier.
- The pharmaceutical formulation of Claim 13, for use in treatment of fibrosis or cancer.
- The pharmaceutical formulation of Claim 13 or 14, for use in combination with an additional therapeutic agent, preferably an immune checkpoint inhibitor, for treatment of cancer.
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