Novel ddr1 antibodies and uses thereof

Abstract

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 .