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 the immunoconjugate is selected from ADC-A, ADC-E, ADC-H, ADC-J, ADC-K, ADC-L, ADC-M, ADC-N, ADC-O, ADC-P, ADC-Q, and ADC-R shown in Table 3. 
     
     
         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, and marginal zone lymphoma. 
     
     
         49 . The method of  claim 42 , wherein the hematological cancer is a non-Hodgkin lymphoma that has undergone Richter's transformation, mantle cell lymphoma, or acute myeloid lymphoma. 
     
     
         50 . 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 (Bc1-2) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor. 
     
     
         51 . The method of  claim 50 , wherein the additional therapeutic agent is selected from the group consisting of ibrutinib, acalabrutinib, venetoclax, everolimus, sapanisertib, and idelalisib. 
     
     
         52 . A method of treating a ROR1-expressing solid tumor 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 the immunoconjugate is selected from ADC-A, ADC-E, ADC-H, ADC-J, ADC-K, ADC-L, ADC-M, ADC-N, ADC-O, ADC-P, ADC-Q, and ADC-R shown in Table 3. 
     
     
         53 . The method of  claim 52 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively. 
     
     
         54 . The method of  claim 52 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7. 
     
     
         55 . The method of  claim 52 , wherein the solid tumor is breast cancer or non-small cell lung cancer. 
     
     
         56 . The method of  claim 52 , wherein the solid tumor is ovarian cancer or osteosarcoma. 
     
     
         57 . The method of  claim 52 , 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 (Bc1-2) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor. 
     
     
         58 . The method of  claim 57 , wherein the additional therapeutic agent is selected from the group consisting of ibrutinib, acalabrutinib, venetoclax, everolimus, sapanisertib, and idelalisib. 
     
     
         59 . An immunoconjugate having the formula of Ab-((L)m-(D))n, wherein:
 Ab is an antibody or an antigen-binding fragment thereof that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1);   L is a linker, and m is 0 or 1;   D is a cytotoxic drug moiety; and   n is an integer from 1 to 10.   
     
     
         60 . A pharmaceutical composition comprising the immunoconjugate of  claim 59  and a pharmaceutically acceptable excipient. 
     
     
         61 . A method of making the immunoconjugate of  claim 59 , comprising:
 providing an antibody or an antigen-binding fragment thereof that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and   conjugating to the antibody a cytotoxic drug moiety selected from the group consisting of an anti-tubulin agent, a DNA alkylating agent, a DNA cross-linking agent, a DNA intercalating agent, and an RNA polymerase II inhibitor;   wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.