NOVEL DDR1 ANTIBODIES AND USES THEREOF
The present disclosure relates to antibodies binding to tumor discoidin domain receptor 1 (DDR1) and the uses of the antibodies in detecting and treating cancer. Thus, in one aspect, the present disclosure provides an isolated monoclonal antibody or an antigen-binding fragment thereof that binds specifically to DDR1. In certain embodiments, the antibody or antigen-binding fragment, when bound to DDR1, modulates the activity of DDR1, i.e., suppresses DDR1.
1 . A monoclonal antibody or antigen-binding fragment thereof that specifically binds to discoidin domain receptor 1 (DDR1) protein, comprising a light chain variable region comprising a LC-CDR1, LC-CDR2 and LC-CDR3 within the light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs:108-128, and a heavy variable region comprising a HC-CDR1, HC-CDR2, and HC-CDR3 within the heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:129-149, or variants thereof wherein one or more of the LC-CDRs and/or HC-CDRs comprises one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.
2 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1, LC-CDR2 and LC-CDR3 are a clone paired-set selected from Table 1 and the HC-CDR1, HC-CDR2, and HC-CDR3 are a clone paired-set selected from Table 2, or variants thereof wherein one or more of the LC-CDRs and/or HC-CDRs comprises one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.
3 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1 comprises the amino acid sequence of SEQ ID NO:11, the LC-CDR2 comprises the amino acid sequence GVF, the LC-CDR3 comprises the amino acid sequence of SEQ ID NO:12, the HC-CDR1 comprises the amino acid sequence of SEQ ID NO:57, the HC-CDR2 comprises the amino acid sequence of SEQ ID NO:58, and the HC-CDR3 comprises the amino acid sequence of SEQ ID NO:59 (DDR1-9), or variants thereof wherein one or more of the LC-CDRs and/or HC-CDRs comprises one, two, or three amino acid substitutions, additions, deletions or combinations thereof.
4 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1 comprises the amino acid sequence of SEQ ID NO:41, the LC-CDR2 comprises the amino acid sequence DAS, the LC-CDR3 comprises the amino acid sequence of SEQ ID NO:42, the HC-CDR1 comprises the amino acid sequence of SEQ ID NO:102, the HC-CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the HC-CDR3 comprises the amino acid sequence of SEQ ID NO:104 (DDR1-32), or variants thereof wherein one or more of the LC-CDRs and/or HC-CDRs comprises one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.
5 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 108-128, and the heavy chain variable region having an amino acid sequence selected from SEQ ID NOs: 129-149.
6 . The monoclonal antibody or antigen-binding fragments thereof of claim 1 , wherein:
(a) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 108 (DDR1-1K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 129 (DDR1-1H);
(b) the light chain variable region comprises the amino acid sequence of SEQ ID NO:
109 (DDR1-3K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 (DDR1-3H);
(c) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 110 (DDR1-5K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 131 (DDR1-5H);
(d) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111 (DDR1-6K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 (DDR1-6H);
(e) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 112 (DDR1-9K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 133 (DDR1-9H);
(f) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113 (DDR1-11K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 134 (DDR1-11H);
(g) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 114 (DDR1-12K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 135 (DDR1-12H);
(h) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115 (DDR1-13K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 136 (DDR1-13H);
(i) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 116 (DDR1-14K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 137 (DDR1-14H);
(j) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 117 (DDR1-15K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 138 (DDR1-15H);
(k) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 118 (DDR1-17K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 139 (DDR1-17H);
(l) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 119 (DDR1-20K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 140 (DDR1-20H);
(m) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 120 (DDR1-21K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 141 (DDR1-21H);
(n) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121 (DDR1-22K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 142 (DDR1-22H);
(o) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 122 (DDR1-23K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 143 (DDR1-23H);
(p) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 123 (DDR1-26K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 144 (DDR1-26H);
(q) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 124 (DDR1-28K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 145 (DDR1-28H);
(r) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125 (DDR1-29K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 146 (DDR1-29H);
(s) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 126 (DDR1-32K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 147 (DDR1-32H);
(t) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127 (DDR1-33K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 148 (DDR1-33H); or
(u) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 128 (DDR1-34K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 149 (DDR1-34H), or p 1 variants thereof comprising a variant light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence of the light chain variable region, and a variant heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence of the heavy chain variable region, wherein the variant specifically binds to DDR1 protein.
7 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 112 (DDR1-9K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 133 (DDR1-9H).
8 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127 (DDR1-33K) and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 148 (DDR1-33H).
9 .- 12 . (canceled)
13 . The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 150 or 151 (DDR1-9hu_Lv1 or DDR1-9hu_Lc2), and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 152 (DDR1-9hu_Hv); or variants thereof, comprising a variant light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence of the light chain variable region, and a variant heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence of the heavy chain variable region amino acid sequence, wherein the variant specifically binds to DDR1 protein.
14 . (canceled)
15 . A monoclonal antibody or antigen-binding fragment thereof, which specifically binds to all or a portion of the epitope or the same epitope specifically bound by the monoclonal antibody or antigen-binding fragment thereof of claim 1 .
16 . (canceled)
17 . An antibody-drug conjugate, comprising the monoclonal antibody or antigen-binding fragment thereof of claim 1 , and an anti-tumor drug, wherein the anti-tumor drug is linked to the antibody or antigen-binding fragment thereof.
18 . (canceled)
19 . The antibody-drug conjugate of claim 0 , wherein said antitumor drug is a toxin, a radioisotope, a cytokine, or an enzyme.
20 . A pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.
21 . One or more polynucleotides that encode the monoclonal antibody or antigen-binding fragment thereof of claim 1 .
22 . A vector comprising the one or more polynucleotides of claim 0 .
23 . (canceled)
24 . A host cell comprising the one or more polynucleotides of claim 0 .
25 . (canceled)
26 . (canceled)
27 . A hybridoma or engineered cell encoding and/or producing the monoclonal antibody of claim 1 .
28 . A process of producing an antibody, comprising culturing the host cell of claim 24 , wherein the host cell is capable of expressing the monoclonal antibody or antigen fragment thereof, comprising culturing the host cell under conditions suitable for expressing the antibody or antigen-binding fragment thereof, and isolating the antibody or antigen binding fragment thereof.
29 . A chimeric antigen receptor (CAR) protein comprising an antibody or antigen-binding fragment thereof of claim 1 .
30 . An isolated nucleic acid that encodes the CAR protein of claim 0 .
31 . A vector comprising the isolated nucleic acid of claim 0 .
32 . (canceled)
33 . An engineered cell comprising the isolated nucleic acid of claim 0 .
34 . (canceled)
35 . A method of treating or ameliorating the effect of a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the antibody or n antigen-binding fragment thereof of claim 1 .
36 .- 44 . (canceled)
45 . The method of claim 35 , wherein the monoclonal antibody or antigen binding fragment thereof further comprises an antitumor drug linked thereto.
46 . (canceled)
47 . A method of treating or ameliorating the effect of fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of the monoclonal antibody or antigen-binding fragment thereof of claim 1 .
48 .- 60 . (canceled)
61 . A host cell comprising the vector of claim 22 .
62 . A method of treating or ameliorating the effect of a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the engineered cell of claim 33 .
63 . A method of treating or ameliorating the effect of a fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of the engineered cell of claim 33 .