US2017253670A1PendingUtilityA1

Common light chains and methods of use

58
Assignee: HOFFMANN LA ROCHEPriority: Nov 20, 2014Filed: May 19, 2017Published: Sep 7, 2017
Est. expiryNov 20, 2034(~8.3 yrs left)· nominal 20-yr term from priority
Inventors:Christian KleinEkkehard MoessnerRalf HossePeter BruenkerPablo UmanaChristiane Neumann
C07K 16/2878C07K 2317/24C07K 16/468C07K 2317/92C07K 2317/33C07K 16/30C07K 2317/73C07K 16/2809C07K 2319/00C07K 16/28C07K 2317/71C07K 2317/41C07K 2317/31A61P 35/00C07K 16/46C07K 2317/515C12N 15/73C07K 16/464A61K 2039/505A61K 39/385A61K 47/48369A61K 39/0011A61K 2039/5158A61K 39/001102A61K 39/00117
58
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention generally relates to novel bispecific antigen binding molecules for T cell activation and re-direction to specific target cells comprising a common light chain. In addition, the present invention relates to polynucleotides encoding such bispecific antigen binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the bispecific antigen binding molecules of the invention, and to methods of using these bispecific antigen binding molecules in the treatment of disease.

Claims

exact text as granted — not AI-modified
1 . A T cell activating bispecific antigen binding molecule comprising a first and a second antigen binding moiety, wherein the first antigen binding moiety comprises a first light chain and wherein the first antigen binding moiety is capable of specific binding to an activating T cell antigen, wherein the second antigen binding moiety comprises a second light chain and wherein the second antigen binding moiety is capable of specific binding to a target cell antigen, wherein the amino acid sequence of the first and the second light chain is identical. 
     
     
         2 . The T cell activating bispecific antigen binding molecule of  claim 1 , wherein the first antigen binding moiety is a Fab. 
     
     
         3 . The T cell activating bispecific antigen binding molecule of  claim 1  or  2 , wherein the second antigen binding moiety is a Fab. 
     
     
         4 . The T cell activating bispecific antigen binding molecule of any one of  claims 1  to  3 , further comprising a third antigen binding moiety capable of specific binding to a target cell antigen. 
     
     
         5 . The T cell activating bispecific antigen binding molecule of  claim 1 , further comprising an Fc domain composed of a first and a second subunit capable of stable association. 
     
     
         6 . The T cell activating bispecific antigen binding molecule of any one of  claims 1  to  5 , wherein the first and the second light chain comprises the light chain CDRs of SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34. 
     
     
         7 . The T cell activating bispecific antigen binding molecule of any one of  claims 1  to  6 , wherein the first and the second light chain comprise a kappa constant light chain domain. 
     
     
         8 . The T cell activating bispecific antigen binding molecule of any one of  claims 1  to  6 , wherein the first and second light chain comprise a lambda constant light chain domain. 
     
     
         9 . The T cell activating bispecific antigen binding molecule of  claim 8 , wherein the first and second light chain is a human or humanized lambda light chain. 
     
     
         10 . The T cell activating bispecific antigen binding molecule of  claim 9 , wherein the first and second light chain is a human or humanized lambda 7 light chain. 
     
     
         11 . The T cell activating bispecific antigen binding molecule of any of  claims 1  to  6  and  8  to  10 , wherein the first and second light chain comprise the amino acid sequence of SEQ ID NO: 31. 
     
     
         12 . The T cell activating bispecific antigen binding molecule of  claim 11 , wherein the first and second light chain comprise the amino acid sequence of SEQ ID NO: 35. 
     
     
         13 . The T cell activating bispecific antigen binding molecule of any of  claims 1  to  8 , wherein said antigen binding moiety capable of specific binding to an activating T cell antigen comprises a heavy chain comprising the heavy chain CDRs of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39. 
     
     
         14 . The T cell activating bispecific antigen binding molecule of any of  claims 1  to  13 , comprising not more than one antigen binding moiety capable of specific binding to an activating T cell antigen. 
     
     
         15 . The T cell activating bispecific antigen binding molecule of any of  claims 1  to  13 , wherein the first and the second antigen binding moiety are fused to each other, optionally via a peptide linker. 
     
     
         16 . The T cell activating bispecific antigen binding molecule of any one of  claims 2  to  13 , wherein the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding moiety. 
     
     
         17 . The T cell activating bispecific antigen binding molecule of any one of  claims 2  to  13 , wherein the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen binding moiety. 
     
     
         18 . The T cell activating bispecific antigen binding molecule of any one of  claims 2  to  13  and  9 , wherein the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain. 
     
     
         19 . The T cell activating bispecific antigen binding molecule of any one of  claims 2  to  13 , wherein the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain. 
     
     
         20 . The T cell activating bispecific antigen binding molecule of any one of  claims 2  to  13 , wherein the first and the second antigen binding moiety are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain. 
     
     
         21 . The T cell activating bispecific antigen binding molecule of  claim 4 , wherein the first, second and third antigen binding moiety are each a Fab molecule comprising an identical VLCL light chain. 
     
     
         22 . The T cell activating bispecific antigen binding molecule of  claim 4  or  21 , wherein the first, second and third antigen binding moiety are each a Fab molecule comprising the light chain CDRs of SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34. 
     
     
         23 . The T cell activating bispecific antigen binding molecule of  claim 4  or  21 , wherein the first, second and third antigen binding moiety are each a Fab molecule comprising a light chain comprising the amino acid sequence of SEQ ID NO: 31. 
     
     
         24 . The T cell activating bispecific antigen binding molecule of any one of  claims 4  or  21  to  23 , wherein the third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain. 
     
     
         25 . The T cell activating bispecific antigen binding molecule of any one of  claims 4  or  21  to  23 , wherein the second and the third antigen binding moiety are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain, and the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen binding moiety. 
     
     
         26 . The T cell activating bispecific antigen binding molecule of  claim 25 , wherein the second and the third antigen binding moiety and the Fc domain are part of an immunoglobulin molecule, particularly an IgG class immunoglobulin. 
     
     
         27 . The T cell activating bispecific antigen binding molecule of any one of  claims 4  or  21  to  23 , wherein the first and the third antigen binding moiety are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain, and the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding moiety. 
     
     
         28 . The T cell activating bispecific antigen binding molecule of  claim 27 , wherein the first and the third antigen binding moiety and the Fc domain are part of an immunoglobulin molecule, particularly an IgG class immunoglobulin. 
     
     
         29 . The T cell activating bispecific antigen binding molecule of any one of  claims 5  to  28 , wherein the Fc domain is an IgG, specifically an IgG 1  or IgG 4 , Fc domain. 
     
     
         30 . The T cell activating bispecific antigen binding molecule of any one of  claims 5  to  25 , wherein the Fc domain is a human Fc domain. 
     
     
         31 . The T cell activating bispecific antigen binding molecule of any one of  claims 5  to  23 , wherein the Fc domain comprises a modification promoting the association of the first and the second subunit of the Fc domain. 
     
     
         32 . The T cell activating bispecific antigen binding molecule of  claim 31 , wherein in the CH3 domain of the first subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable. 
     
     
         33 . The T cell activating bispecific antigen binding molecule of any one of  claims 5  to  32 , wherein the Fc domain exhibits reduced binding affinity to an Fc receptor and/or reduced effector function, as compared to a native IgG1 Fc domain. 
     
     
         34 . The T cell activating bispecific antigen binding molecule of any one of  claims 5  to  32 , wherein the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor and/or effector function. 
     
     
         35 . The T cell activating bispecific antigen binding molecule of  claim 34 , wherein said one or more amino acid substitution is at one or more position selected from the group of L234, L235, and P329. 
     
     
         36 . The T cell activating bispecific antigen binding molecule of  claim 34 , wherein each subunit of the Fc domain comprises three amino acid substitutions that reduce binding to an activating Fc receptor and/or effector function wherein said amino acid substitutions are L234A, L235A and P329G. 
     
     
         37 . The T cell activating bispecific antigen binding molecule of any one of  claims 33  to  36 , wherein the Fc receptor is an Fcγ receptor. 
     
     
         38 . The T cell activating bispecific antigen binding molecule of any one of  claims 33  to  37 , wherein the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC). 
     
     
         39 . The T cell activating bispecific antigen binding molecule of any one of the preceding claims, wherein the activating T cell antigen is CD3. 
     
     
         40 . The T cell activating bispecific antigen binding molecule of any one of the preceding claims, wherein the target cell antigen is selected from the group consisting of: Folate Receptor 1 (FolR1), Mucin-1 (MUC1), and B Cell Maturation Antigen (BCMA). 
     
     
         41 . The T cell activating bispecific antigen binding molecule of any one of the preceding claims, wherein the first and the second light chain is a humanized light chain. 
     
     
         42 . The T cell activating bispecific antigen binding molecule of any one of the preceding claims, wherein the first and the second light chain are capable of use in more than two antigen binding moieties having different antigen specificity. 
     
     
         43 . The T cell activating bispecific antigen binding molecule of any of the preceding claims, wherein the target cell antigen is not BCMA. 
     
     
         44 . A light chain comprising the amino acid sequence of SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34 for use in a T cell activating bispecific antigen binding molecule. 
     
     
         45 . The light chain of  claim 44  which comprises a kappa constant light chain domain. 
     
     
         46 . The light chain of  claim 44  which comprises a lambda constant light chain domain. 
     
     
         47 . The light chain of  claim 46  which is a human or humanized lambda light chain. 
     
     
         48 . The light chain of  claim 46  which is a human or humanized lambda 7 light chain. 
     
     
         49 . The light chain of any one of  claims 46  to  48  comprising the amino acid sequence of SEQ ID NO: 31. 
     
     
         50 . The light chain of  claim 49  comprising the amino acid sequence of SEQ ID NO: 35. 
     
     
         51 . A light chain comprising the amino acid sequence of SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34 for use in a library for production of T cell activating bispecific antigen binding molecule. 
     
     
         52 . The light chain of  claim 51  which comprises a kappa constant light chain domain. 
     
     
         53 . The light chain of  claim 51  which comprises a lambda constant light chain domain. 
     
     
         54 . The light chain of  claim 53  which is a human or humanized lambda light chain. 
     
     
         55 . The light chain of  claim 54  which is a human or humanized lambda 7 light chain. 
     
     
         56 . The light chain of any one of  claims 53  to  55  comprising the amino acid sequence of SEQ ID NO: 31. 
     
     
         57 . The light chain of  claim 56  comprising the amino acid sequence of SEQ ID NO: 35. 
     
     
         58 . An isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 31. 
     
     
         59 . An isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 35. 
     
     
         60 . An isolated polynucleotide encoding the T cell activating bispecific antigen binding molecule of any one of  claims 1  to  41  or a fragment thereof or the isolated polypeptide of  claim 58  or  59  or a fragment thereof. 
     
     
         61 . A polypeptide encoded by the isolated polynucleotide of  claim 60 . 
     
     
         62 . A vector, particularly an expression vector, comprising the isolated polynucleotide of  claim 60 . 
     
     
         63 . A host cell comprising the isolated polynucleotide of  claim 60  or the vector of  claim 62 . 
     
     
         64 . A method of producing the T cell activating bispecific antigen binding molecule of any one of  claims 1  to  43 , comprising the steps of a) culturing the host cell of  claim 63  under conditions suitable for the expression of the T cell activating bispecific antigen binding molecule and b) recovering the T cell activating bispecific antigen binding molecule. 
     
     
         65 . A T cell activating bispecific antigen binding molecule produced by the method of  claim 64 . 
     
     
         66 . A pharmaceutical composition comprising the T cell activating bispecific antigen binding molecule of any one of  claims 1  to  43  and a pharmaceutically acceptable carrier. 
     
     
         67 . A method of treating a disease in an individual, comprising administering to said individual a therapeutically effective amount of a composition comprising the T cell activating bispecific antigen binding molecule of any one of  claims 1  to  43  or the light chain of any one of  claims 44  to  57  in a pharmaceutically acceptable form. 
     
     
         68 . The method of  claim 67 , wherein said disease is cancer. 
     
     
         69 . A method for inducing lysis of a target cell, comprising contacting a target cell with the T cell activating bispecific antigen binding molecule of any one of  claims 1  to  43  in the presence of a T cell. 
     
     
         70 . A method for identifying a variable heavy chain for use in a bispecific antigen binding molecule specific for a T cell activation antigen and a target cell antigen, comprising the step of screening a combinatorial library comprising variable heavy chains with a light chain comprising the amino acid sequence of SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34. 
     
     
         71 . The method of  claim 70 , wherein the light chain comprises a kappa constant light chain domain. 
     
     
         72 . The method of  claim 70 , wherein the light chain comprises a lambda constant light chain domain. 
     
     
         73 . The method of  claim 72 , wherein the light chain is a human or humanized lambda light chain. 
     
     
         74 . The light chain of  claim 73  which is a human or humanized lambda 7 light chain. 
     
     
         75 . The method of any one of  claims 72  to  74 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 31. 
     
     
         76 . The method of  claim 75 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 35.

Join the waitlist — get patent alerts

Track US2017253670A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.