Multivalent and Monovalent Multispecific Complexes and Their Uses

Abstract

Compositions containing multivalent and monovalent multispecific complexes having scaffolds such as antibodies that support such binding functionalities are described. The use of and methods of compositions containing multivalent and monovalent multispecific complexes having scaffolds, such as antibodies, that support such binding functionalities are also described.

1 . A complex comprising an antibody and at least one modular recognition domain (MRD), wherein the antibody and the MRD bind to different targets or epitopes on the same cell or molecule, wherein the MRD binding agonizes or antagonizes the MRD target under physiological conditions, and wherein said MRD does not bind to and agonize or antagonize said MRD target under physiological conditions in the absence of said antibody. 
     
     
         2 . The complex of  claim 1 , wherein in the absence of said antibody, the MRD binds the MRD target with an EC50 of greater than 0.01, 0.1, 0.5 or 0.7 nM under physiological conditions. 
     
     
         3 . The complex of  claim 1 , wherein the antibody and the MRD bind to different targets or epitopes on a heteromeric or homomeric protein. 
     
     
         4 . A method for inhibiting the growth of a cell comprising contacting the cell with a multispecific and multivalent complex comprising an antibody and at least one modular recognition domain (MRD), and a protein kinase inhibitor. 
     
     
         5 . A method for inhibiting angiogenesis in a patient comprising administering to said patient a therapeutically effective amount of a multispecific and multivalent complex comprising an antibody and at least one modular recognition domain (MRD), and a protein kinase inhibitor. 
     
     
         6 . The method of  claim 4 , wherein the antibody binds a target selected from: VEGF, VEGFR1, EGFR, ErbB2, cMET, FGFR1, and FGFR2. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 4 , wherein the protein kinase inhibitor is a member selected from: imatinib, gefitinib, vandetanib, erlotinib, sunitinib, lapatinib, and sorafenib. 
     
     
         11 . A method for treating a patient having a disease or disorder comprising administering to said patient a therapeutically effective amount of a multispecific and multivalent complex comprising an antibody and at least one modular recognition domain (MRD), and a protein kinase inhibitor. 
     
     
         12 . The method of  claim 11 , wherein the disease or disorder is cancer. 
     
     
         13 . The method of  claim 11 , wherein the disease or disorder is a disease or disorder of the immune system. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 11 , wherein the antibody binds to a target selected from: TNF, VEGF, VEGFR1, EGFR, ErbB2, IGF-IR, cMET, FGFR1, FGFR2, and CD20. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 11 , wherein the protein kinase inhibitor is a member selected from: imatinib, gefitinib, vandetanib, erlotinib, sunitinib, lapatinib, and sorafenib. 
     
     
         21 . The method of  claim 11 , wherein the protein kinase inhibitor is a member selected from: lestaurtinib, tofacitinib, ruxolitinib, SB1518, CYT387, LY3009104, TG101348, fostamatinib, BAY 61-3606, and sunitinib. 
     
     
         22 . A multivalent and multispecific complex comprising an antibody and at least one modular recognition domain (MRD), wherein the complex has a single binding site for a cell surface target. 
     
     
         23 . (canceled) 
     
     
         24 . The complex of  claim 22 , wherein the complex has 2, 3, 4, 5 or more single binding sites for different targets. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . The complex of  claim 22 , wherein the complex has multiple binding sites for a target on a diseased cell. 
     
     
         31 . (canceled) 
     
     
         32 . The complex of  claim 22 , wherein the complex has multiple binding sites for a target on a tumor cell. 
     
     
         33 . (canceled) 
     
     
         34 . The complex of  claim 22 , wherein the complex has multiple binding sites for a target on an immune cell. 
     
     
         35 . (canceled) 
     
     
         36 . The complex of  claim 22 , wherein the complex binds a target on a leukocyte and a target on a tumor cell. 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . The complex of  claim 22 , wherein the complex has a binding site for a target associated with an endogenous blood brain barrier (BBB) receptor mediated transport system. 
     
     
         41 . The complex of  claim 40 , wherein the complex has multiple binding sites for a target associated with an endogenous BBB receptor mediated transport system. 
     
     
         42 . (canceled) 
     
     
         43 . The complex of  claim 22 , wherein the single binding site is an MRD. 
     
     
         44 . The complex of  claim 22 , wherein the single binding site is an antigen binding domain. 
     
     
         45 . (canceled) 
     
     
         46 . A polynucleotide encoding a heavy chain or light chain of the MRD containing antibody in the complex of  claim 22 . 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . A pharmaceutical composition comprising the complex of  claim 22 . 
     
     
         50 . A method for inhibiting the growth of a cell comprising contacting the cell with the complex of  claim 22 . 
     
     
         51 . A method for inhibiting angiogenesis in a patient comprising administering to said patient a therapeutically effective amount of the complex of  claim 22 . 
     
     
         52 . A method for treating a patient having cancer comprising administering to said patient a therapeutically effective amount of the complex of  claim 22 . 
     
     
         53 . A method for treating a patient having a disease or disorder of the immune system comprising administering to said patient a therapeutically effective amount of the complex of  claim 22 .