Ror1 antibody immunoconjugates

Abstract

Provided herein are immunoconjugates comprising an anti-ROR1 antibody or an antigen-fragment fragment thereof and a drug moiety. These immunoconjugates are useful for treating ROR1 expressing cancers.

1 - 41 . (canceled) 
     
     
         42 . A method of treating a ROR1-expressing hematological cancer in a patient in need thereof, comprising administering to the patient an immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety,
 wherein the V H  and V L  of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and   wherein the cytotoxic drug moiety is
 (i) monomethyl auristatin E (MMAE) and is conjugated to the antibody at a lysine residue via a linker comprising valine-citrulline (VC) and para-amino-benzyloxycarbonyl (PAB) moieties; 
 (ii) MMAE and is conjugated to the antibody at a cysteine residue via a linker comprising diaminopropionic acid (DPR), VC, and PAB moieties; 
 (iii) MMAE and is conjugated to the antibody at a cysteine residue via a linker comprising benzyl (Phe)-C 4 , VC, and PAB moieties; 
 (iv) MMAE and is conjugated to the antibody at a glutamine residue via a branched linker comprising dibenzylcyclooctyne (DBCO), polyethylene glycol (PEG) 2 , VC, and PAB moieties; 
 (v) azonafide and is conjugated to the antibody at a cysteine residue via a linker comprising VC and PAB moieties; 
 (vi) duocarmycin and is conjugated to the antibody at a cysteine residue via a linker comprising PEG 4 , VC, PAB, and dimethylethylamine (DMEA) moieties; 
 (vii) pyrrolobenzodiazepine (PBD) and is conjugated to the antibody at a cysteine residue via a linker comprising PEG 4  and valine-alanine (VA) moieties; 
 (viii) PNU-159682 and is conjugated to the antibody at a cysteine residue via a linker comprising PEG 4 , VC, PAB, and DMEA moieties; 
 (ix) PNU-159682 and is conjugated to the antibody at a cysteine residue via a linker comprising C 2 -glycine (Gly) 3 , and ethylene diamine (EDA) moieties; 
 (x) PNU-159682 and is conjugated to the antibody at a cysteine residue via a linker comprising Phe-C 4 , VC, PAB, and DMEA moieties; or 
 (xi) PNU-159682 and is conjugated to the antibody at a glutamine residue via a linker comprising PEG 4 , VC, PAB, and DMEA moieties. 
   
     
     
         43 . The method of  claim 42 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively. 
     
     
         44 . The method of  claim 42 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7. 
     
     
         45 . The method of  claim 42 , wherein the hematological cancer is a lymphoma. 
     
     
         46 . The method of  claim 42 , wherein the hematological cancer is a leukemia. 
     
     
         47 . The method of  claim 42 , wherein the hematological cancer is a non-Hodgkin lymphoma. 
     
     
         48 . The method of  claim 47 , wherein the non-Hodgkin lymphoma is selected from diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, acute myeloid lymphoma, marginal zone lymphoma, and any non-Hodgkin lymphoma that has undergone Richter's transformation. 
     
     
         49 . The method of  claim 42 , further comprising administering an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor. 
     
     
         50 . The method of  claim 49 , wherein the additional therapeutic agent is selected from the group consisting of ibrutinib, acalabrutinib, venetoclax, everolimus, sapanisertib, and idelalisib. 
     
     
         51 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a lysine residue. 
       
     
     
         52 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         53 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         54 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         55 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         56 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         57 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         58 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         59 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a cysteine residue. 
       
     
     
         60 . The method of  claim 42 , wherein the immunoconjugate has the structure 
       
         
           
           
               
               
           
         
         wherein Ab is the antibody and the linker is conjugated to the antibody at a glutamine residue. 
       
     
     
         61 . A method of treating a ROR1-expressing hematological cancer in a patient in need thereof, comprising administering to the patient an immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety,
 wherein the V H  and V L  of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and   wherein the cytotoxic drug moiety (D) is conjugated to the antibody as shown in the following structure   
       
         
           
           
               
               
           
         
         wherein Ab is the antibody, the linker is conjugated to the antibody at a lysine residue, and the cytotoxic drug moiety (D) is MMAE