Ror1 antibody compositions and related methods

Abstract

The invention provides antibodies, antibody drug conjugates, antibody-based fragments or antibody fragments (antigen-binding fragments), as well as antibody drug conjugates (ADCs) and chimeric antigen receptors (CARs), that specifically recognize human ROR1 and related compositions. Also provided in the invention are methods of using such antibodies in various diagnostic and therapeutic applications.

We claim: 
     
         1 . An antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), comprising heavy chain CDR1, CDR2 and CDR3 sequences and light chain CDR1, CDR2 and CDR3 sequences respectively set forth as
 (1) SEQ ID NOs:27-29 and SEQ ID NOs:66-68,   (2) SEQ ID NOs:30-32 and SEQ ID NOs:69-71,   (3) SEQ ID NOs:33-35 and SEQ ID NOs:72-74,   (4) SEQ ID NOs:36-38 and SEQ ID NOs:75-77,   (5) SEQ ID NOs:39-41 and SEQ ID NOs:78-80,   (6) SEQ ID NOs:42-44 and SEQ ID NOs:81-83,   (7) SEQ ID NOs:45-47 and SEQ ID NOs:84-86,   (8) SEQ ID NOs:48-50 and SEQ ID NOs:87-89,   (9) SEQ ID NOs:51-53 and SEQ ID NOs:90-92,   (10) SEQ ID NOs:54-56 and SEQ ID NOs:93-95,   (11) SEQ ID NOs:57-59 and SEQ ID NOs:96-98,   (12) SEQ ID NOs:60-62 and SEQ ID NOs:99-101, or   (13) SEQ ID NOs:63-65 and SEQ ID NOs:102-104.   
     
     
         2 . The antibody, antibody-based binding protein or antibody fragment of  claim 1 , comprising a light chain CDR sequence selected from the group consisting of SEQ ID NOs:66-104. 
     
     
         3 . The antibody, antibody-based binding protein or antibody fragment of  claim 1 , further comprising a heavy chain CDR sequence selected from the group consisting of SEQ ID NOs:27-65. 
     
     
         4 . The antibody, antibody-based binding protein or antibody fragment of  claim 1 , comprising light chain CDR1, CDR2, and CDR3 sequences that are respectively identical to SEQ ID NOs:66-68, SEQ ID NOs:69-71, SEQ ID NOs:72-74, SEQ ID NO:75-77, SEQ ID NOs:78-80, SEQ ID NOs:81-83, SEQ ID NOs:84-86, SEQ ID NOs:87-89, SEQ ID NOs:90-92, SEQ ID NOs:93-95, SEQ ID NOs:96-98, SEQ ID NOs:99-101, or SEQ ID NOs:102-104. 
     
     
         5 . The antibody, antibody-based binding protein or antibody fragment of  claim 1 , wherein the antibody, antibody-based binding protein or antibody fragment is fused to a transmembrane region and an intracellular T-cell receptor (TCR) signaling domain to form a chimeric antigen receptor (CAR). 
     
     
         6 . A polynucleotide encoding the antibody, antibody-based binding protein or antibody fragment of  claim 1 . 
     
     
         7 . A pharmaceutical composition comprising (1) a therapeutically effective amount of the antibody, antibody-based binding protein or antibody fragment of  claim 1  and (2) a pharmaceutically acceptable carrier. 
     
     
         8 . A method of treating a disease or condition associated with elevated expression of ROR1 in a subject, comprising administering the pharmaceutical composition of  claim 7  to a subject having a disease or condition associated with elevated expression of ROR1, thereby treating the disease or condition associated with elevated expression of ROR1 in the subject. 
     
     
         9 . An antibody drug conjugate (ADC), comprising
 (i) an antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), comprising heavy chain CDR1, CDR2 and CDR3 sequences and light chain CDR1, CDR2 and CDR3 sequences respectively set forth as   (1) SEQ ID NOs:27-29 and SEQ ID NOs:66-68,   (2) SEQ ID NOs:30-32 and SEQ ID NOs:69-71,   (3) SEQ ID NOs:33-35 and SEQ ID NOs:72-74,   (4) SEQ ID NOs:36-38 and SEQ ID NOs:75-77,   (5) SEQ ID NOs:39-41 and SEQ ID NOs:78-80,   (6) SEQ ID NOs:42-44 and SEQ ID NOs:81-83,   (7) SEQ ID NOs:45-47 and SEQ ID NOs:84-86,   (8) SEQ ID NOs:48-50 and SEQ ID NOs:87-89,   (9) SEQ ID NOs:51-53 and SEQ ID NOs:90-92,   (10) SEQ ID NOs:54-56 and SEQ ID NOs:93-95,   (11) SEQ ID NOs:57-59 and SEQ ID NOs:96-98,   (12) SEQ ID NOs:60-62 and SEQ ID NOs:99-101, or   (13) SEQ ID NOs:63-65 and SEQ ID NOs:102-104,   
       and
 (ii) at least one cytotoxic agent. 
 
     
     
         10 . The antibody drug conjugate of  claim 9 , wherein the cytotoxic agent is a small molecular weight toxin, a peptide toxin, or a protein toxin. 
     
     
         11 . The antibody drug conjugate of  claim 9 , wherein the antibody or antibody fragment is conjugated to the cytotoxic agent via sortase enzyme mediated antibody conjugation (SMAC). 
     
     
         12 . The antibody drug conjugate of  claim 9 , wherein the cytotoxic agent is anthracycline (PNU) toxin derivative Gly (n) -EDA-PNU, where n is any number from 1 to 21. 
     
     
         13 . The antibody drug conjugate of  claim 9 , wherein the antibody or antibody fragment comprises heavy chain CDR1, CDR2 and CDR3 sequences and light chain CDR1, CDR2 and CDR3 sequences respectively shown in
 (1) SEQ ID NOs:27-29 and SEQ ID NOs:66-68,   (2) SEQ ID NOs:39-41 and SEQ ID NOs:78-80 or   (3) SEQ ID NOs:60-62 and SEQ ID NOs:99-101.   
     
     
         14 . A method of killing or inhibiting the growth of a tumor cell expressing ROR1 in a subject, comprising administering the pharmaceutical composition of  claim 9  to a subject in need thereof, thereby killing or inhibiting the growth of the tumor cell expressing ROR1 in the subject. 
     
     
         15 . A humanized antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), comprising a heavy chain variable region sequence and a light chain variable region sequence respectively set forth as
 (1) SEQ ID NO:130 and SEQ ID NO:136;   (2) SEQ ID NO:131 and SEQ ID NO:137;   (3) SEQ ID NO:132 and SEQ ID NO:138;   (4) SEQ ID NO:133 and SEQ ID NO:139;   (5) SEQ ID NO:134 and SEQ ID NO:140; or   (6) SEQ ID NO:135 and SEQ ID NO:141.   
     
     
         16 . The antibody, antibody-based binding protein or antibody fragment of  claim 15 , wherein the antibody, antibody-based binding protein or antibody fragment is fused to a transmembrane region and an intracellular T-cell receptor (TCR) signaling domain to form a chimeric antigen receptor (CAR). 
     
     
         17 . A polynucleotide encoding the antibody, antibody-based binding protein or antibody fragment of  claim 15 . 
     
     
         18 . A pharmaceutical composition comprising (1) a therapeutically effective amount of the antibody, antibody-based binding protein or antibody fragment of  claim 15  and (2) a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treating a disease or condition associated with elevated expression of ROR1 in a subject, comprising administering the pharmaceutical composition of  claim 15  to a subject having a disease or condition associated with elevated expression of ROR1, thereby treating the disease or condition associated with elevated expression of ROR1 in the subject. 
     
     
         20 . A humanized antibody drug conjugate (hADC), comprising
 (i) a humanized antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), comprising a heavy chain variable region sequence and a light chain variable region sequence respectively set forth as   (1) SEQ ID NO:130 and SEQ ID NO:136;   (2) SEQ ID NO:131 and SEQ ID NO:137;   (3) SEQ ID NO:132 and SEQ ID NO:138;   (4) SEQ ID NO:133 and SEQ ID NO:139;   (5) SEQ ID NO:134 and SEQ ID NO:140; or   (6) SEQ ID NO:135 and SEQ ID NO:141,   
       and
 (ii) at least one cytotoxic agent. 
 
     
     
         21 . The antibody drug conjugate of  claim 20 , wherein the cytotoxic agent is a small molecular weight toxin, a peptide toxin, or a protein toxin. 
     
     
         22 . The antibody drug conjugate of  claim 20 , wherein the humanized antibody or antibody fragment is conjugated to the cytotoxic agent via sortase enzyme mediated antibody conjugation (SMAC). 
     
     
         23 . The antibody drug conjugate of  claim 20 , wherein the cytotoxic agent is anthracycline (PNU) toxin derivative Gly (n) -EDA-PNU, where n is any number from 1 to 21.