Chimeric rabbit/human ror1 antibodies

Abstract

The invention relates to antibodies having specificity for human ROR1, compositions thereof, and methods for using such antibodies, including in the diagnosis and treatment of disorders associated with aberrant ROR1 expression.

1 . An isolated antibody having specificity for the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), wherein the antibody comprises:
 (a) a light chain variable domain having at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, and SEQ ID NO: 5; or   (b) a heavy chain variable domain having at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 4, and SEQ ID NO: 6; or   (c) both a light chain of (a) and a heavy chain of (b).   
     
     
         2 .- 33 . (canceled) 
     
     
         34 . A method of killing or inhibiting the growth of cells expressing ROR1 in a subject, which method comprises administering a therapeutically effective amount of an isolated antibody of  claim 1  to a subject in need thereof, thereby killing or inhibiting the growth of cells expressing ROR1 in the subject. 
     
     
         35 . A method of treating a disease or condition associated with elevated expression of ROR1 in a subject, the method comprising administering a therapeutically effective amount of an antibody of  claim 1  to a subject in need thereof, which subject has 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. 
     
     
         36 . The method of  claim 35 , wherein the disease or condition is a B-cell cancer, renal cell carcinoma, colon cancer, colorectal cancer, or breast cancer. 
     
     
         37 . The method of  claim 36 , wherein the disease or condition is B-cell lymphocytic leukemia (B-CLL) or mantle cell lymphoma (MCL). 
     
     
         38 . The method of  claim 34 , wherein the antibody is selected from the group consisting of an F(ab)2, Fv, scFv, IgGΔCH2, F(ab′)2, scFv2CH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, (scFv)2, and a synthetic IgG. 
     
     
         39 . The method of  claim 38 , wherein the antibody is conjugated to a synthetic molecule. 
     
     
         40 . The method of  claim 39 , wherein the antibody is a T-body and the synthetic molecule comprises a transmembrane region and an intracellular T-cell receptor (TCR) signaling domain. 
     
     
         41 . The method of  claim 39 , wherein the synthetic molecule is a cytotoxic agent, a radioisotope, or a liposome. 
     
     
         42 . The method of  claim 34 , wherein the method further comprises co-administering a pharmaceutical composition comprising a second therapeutic agent to kill or inhibit the growth of cells expressing ROR1 or to treat the disease or condition associated with elevated expression of ROR1 in the subject. 
     
     
         43 . A method of detecting an altered ROR1 level in a test sample, which method comprises:
 (a) obtaining a test sample from a subject;   (b) contacting the sample with an isolated antibody of  claim 1 ;   (c) determining the level of ROR1 in the test sample; and   (d) comparing the level of ROR1 in the test sample to a control level of ROR1 to thereby determine whether the ROR1 level in the test sample is altered relative to the control level of ROR1.   
     
     
         44 . The method of  claim 43 , wherein a level of ROR1 in the subject that is greater than the control level is indicative of a disease or condition associated with elevated expression of ROR1 in the subject. 
     
     
         45 . The method of  claim 44 , wherein the disease or condition associated with elevated expression of ROR1 is a B-cell cancer, renal cell carcinoma, colon cancer, colorectal cancer, or breast cancer. 
     
     
         46 . The method of  claim 44 , wherein the disease or condition is B-cell lymphocytic leukemia (B-CLL) or mantle cell lymphoma (MCL). 
     
     
         47 . A method of detecting an ROR1-expressing tumor in a subject, which method comprises:
 (a) administering the antibody of  claim 1  to a subject that has, is suspected to have, or is at risk for an ROR1-expressing tumor; and   (b) imaging the subject for a region of altered conjugated label density or concentration, wherein the density or concentration is relative to (i) background in proximal tissue or (ii) the density or concentration previously detected in the same region of the subject, such that the existence of a region of altered conjugated label density or concentration is an indication of the presence of an ROR1-expressing tumor in the subject.   
     
     
         48 . A method of detecting an ROR1-expressing B-cell tumor in a subject, which method comprises:
 (a) administering the antibody of  claim 1  to a subject that has, is suspected to have, or is at risk for a B-cell tumor; and   (b) imaging the subject for a region of altered conjugated label density or concentration, wherein the density or concentration is relative to (i) background in proximal tissue or (ii) the density or concentration previously detected in the same region of the subject, such that the existence of a region of altered conjugated label density or concentration is an indication of the presence of an ROR1-expressing B-cell tumor in the subject.   
     
     
         49 . The method of  claim 48 , wherein the ROR1-expressing B-cell tumor is a B-cell lymphocytic leukemia (B-CLL) or a mantle cell lymphoma (MCL) tumor.